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1.	Jaravine, Victor, 1966, et al. (författare) Hyper-dimensional NMR spectroscopy with nonlinear sampling 2008 Ingår i: Journal of the American Chemical Society. ; 130:12, s. 3927-3936 Tidskriftsartikel (refereegranskat)abstract An approach is described for joint interleaved recording, real-time processing, and analysis of NMR data sets. The method employs multidimensional decomposition to find common information in a set of conventional triple-resonance spectra recorded in the nonlinear sampling mode, and builds a model of hyperdimensional (HD) spectrum. While preserving sensitivity per unit of measurement time and allowing for maximal spectral resolution, the approach reduces data collection time on average by 2 orders of magnitude compared to the conventional method. The 7-10 dimensional HD spectrum, which is represented as a set of deconvoluted 1D vectors, is easy to handle and amenable for automated analysis. The method is exemplified by automated assignment for two protein systems of low and high spectral complexity: ubiquitin (globular, 8 kDa) and cyt (naturally disordered, 13 kDa). The collection and backbone assignment of the data sets are achieved in real time after approximately 1 and 10 h, respectively. The approach removes the most critical time bottlenecks in data acquisition and analysis. Thus, it can significantly increase the value of NMR spectroscopy in structural biology, for example, in high-throughput structural genomics applications.
2.	Jaravine, Victor, 1966, et al. (författare) Removal of a time barrier for high-resolution multidimensional NMR spectroscopy 2006 Ingår i: Nature Methods. - 1548-7091. ; 3:8, s. 605-607 Tidskriftsartikel (refereegranskat)abstract We introduce a recursive multi-dimensional decomposition (R-MDD) method to speed-up recording of high-resolution NMR spectra. This method has a logarithmic dependence of measurement time on the size of indirect spectral dimensions, enjoys sensitivity and resolution advantages of optimized non-uniform acquisition schemes, and is applicable to all types of spectra of biomolecules. We demonstrate performance for several triple resonance experiments recorded on three globular proteins with molecular weights 8-22 kDa.
3.	Jaravine, Victor, 1966, et al. (författare) Targeted acquisition for real-time NMR spectroscopy 2006 Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 128:41, s. 13421-13426 Tidskriftsartikel (refereegranskat)
4.	Luan, Tu, 1973, et al. (författare) Optimization of resolution and sensitivity of 4D NOESY using multi-dimensional decomposition 2005 Ingår i: Journal of Biomolecular NMR. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 33:1, s. 1-14 Tidskriftsartikel (refereegranskat)
5.	Tikole, S., et al. (författare) Effects of NMR Spectral Resolution on Protein Structure Calculation 2013 Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7 Tidskriftsartikel (refereegranskat)abstract Adequate digital resolution and signal sensitivity are two critical factors for protein structure determinations by solution NMR spectroscopy. The prime objective for obtaining high digital resolution is to resolve peak overlap, especially in NOESY spectra with thousands of signals where the signal analysis needs to be performed on a large scale. Achieving maximum digital resolution is usually limited by the practically available measurement time. We developed a method utilizing non-uniform sampling for balancing digital resolution and signal sensitivity, and performed a large-scale analysis of the effect of the digital resolution on the accuracy of the resulting protein structures. Structure calculations were performed as a function of digital resolution for about 400 proteins with molecular sizes ranging between 5 and 33 kDa. The structural accuracy was assessed by atomic coordinate RMSD values from the reference structures of the proteins. In addition, we monitored also the number of assigned NOESY cross peaks, the average signal sensitivity, and the chemical shift spectral overlap. We show that high resolution is equally important for proteins of every molecular size. The chemical shift spectral overlap depends strongly on the corresponding spectral digital resolution. Thus, knowing the extent of overlap can be a predictor of the resulting structural accuracy. Our results show that for every molecular size a minimal digital resolution, corresponding to the natural linewidth, needs to be achieved for obtaining the highest accuracy possible for the given protein size using state-of-the-art automated NOESY assignment and structure calculation methods.
6.	Wong, L. E., et al. (författare) Automatic assignment of protein backbone resonances by direct spectrum inspection in targeted acquisition of NMR data 2008 Ingår i: Journal of Biomolecular Nmr. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 42:2, s. 77-86 Tidskriftsartikel (refereegranskat)abstract The necessity to acquire large multidimensional datasets, a basis for assignment of NMR resonances, results in long data acquisition times during which substantial degradation of a protein sample might occur. Here we propose a method applicable for such a protein for automatic assignment of backbone resonances by direct inspection of multidimensional NMR spectra. In order to establish an optimal balance between completeness of resonance assignment and losses of cross-peaks due to dynamic processes/degradation of protein, assignment of backbone resonances is set as a stirring criterion for dynamically controlled targeted nonlinear NMR data acquisition. The result is demonstrated with the 12 kDa C-13,(15) N-labeled apo-form of heme chaperone protein CcmE, where hydrolytic cleavage of 29 C-terminal amino acids is detected. For this protein, 90 and 98% of manually assignable resonances are automatically assigned within 10 and 40 h of nonlinear sampling of five 3D NMR spectra, respectively, instead of 600 h needed to complete the full time domain grid. In addition, resonances stemming from degradation products are identified. This study indicates that automatic resonance assignment might serve as a guiding criterion for optimal run-time allocation of NMR resources in applications to proteins prone to degradation.
7.	Agback, Peter, et al. (författare) H-1, C-13 and N-15 resonance assignment of backbone and IVL-methyl side chain of the S135A mutant NS3pro/NS2B protein of Dengue II virus reveals unique secondary structure features in solution 2022 Ingår i: Biomolecular Nmr Assignments. - : Springer Science and Business Media LLC. - 1874-2718 .- 1874-270X. ; 16, s. 135-145 Tidskriftsartikel (refereegranskat)abstract The serotype II Dengue (DENV 2) virus is the most prevalent of all four known serotypes. Herein, we present nearly complete H-1, N-15, and C-13 backbone and H-1, C-13 isoleucine, valine, and leucine methyl resonance assignment of the apo S135A catalytically inactive variant of the DENV 2 protease enzyme folded as a tandem formed between the serine protease domain NS3pro and the cofactor NS2B, as well as the secondary structure prediction of this complex based on the assigned chemical shifts using the TALOS-N software. Our results provide a solid ground for future elucidation of the structure and dynamic of the apo NS3pro/NS2B complex, key for adequate development of inhibitors, and a thorough molecular understanding of their function(s).
8.	Agback, Peter, et al. (författare) Structural characterization and biological function of bivalent binding of CD2AP to intrinsically disordered domain of chikungunya virus nsP3 protein 2019 Ingår i: Virology. - : Elsevier BV. - 0042-6822 .- 1178-122X. ; 537, s. 130-142 Tidskriftsartikel (refereegranskat)abstract Alphavirus nsP3 proteins contain long, intrinsically disordered, hypervariable domains, HVD, which serve as hubs for interaction with many cellular proteins. Here, we have deciphered the mechanism and function of HVD interaction with host factors in alphavirus replication. Using NMR spectroscopy, we show that CHIKV HVD contains two SH3 domain-binding sites. Using an innovative chemical shift perturbation signature approach, we demonstrate that CD2AP interaction with HVD is mediated by its SH3-A and SH3–C domains, and this leaves the SH3–B domain available for interaction with other cellular factor(s). This cooperative interaction with two SH3 domains increases binding affinity to CD2AP and possibly induces long-range allosteric effects in HVD. Our data demonstrate that BIN1, CD2AP and SH3KBP1 play redundant roles in initiation of CHIKV replication. Point mutations in both CHIKV HVD binding sites abolish its interaction with all three proteins, CD2AP, BIN1 and SH3KBP1. This results in strong inhibition of viral replication initiation. © 2019 Elsevier Inc.
9.	Agback, Tatiana, et al. (författare) Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro 2023 Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1 Tidskriftsartikel (refereegranskat)abstract The dengue protease NS2B/NS3pro has been reported to adopt either an 'open' or a 'closed' conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the 'closed' conformational ensemble while the 'open' conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a 'partially' open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery. A conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution suggests dengue protease NS2B/NS3pro predominantly exists in a "closed" conformation.
10.	Chen, D. C., et al. (författare) Review and Prospect: Deep Learning in Nuclear Magnetic Resonance Spectroscopy 2020 Ingår i: Chemistry-a European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 26:46, s. 10391-10401 Tidskriftsartikel (refereegranskat)abstract Since the concept of deep learning (DL) was formally proposed in 2006, it has had a major impact on academic research and industry. Nowadays, DL provides an unprecedented way to analyze and process data with demonstrated great results in computer vision, medical imaging, natural language processing, and so forth. Herein, applications of DL in NMR spectroscopy are summarized, and a perspective for DL as an entirely new approach that is likely to transform NMR spectroscopy into a much more efficient and powerful technique in chemistry and life sciences is outlined.
11.	Ciudad, S., et al. (författare) A beta(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage 2020 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Formation of amyloid-beta (A beta) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimers disease (AD). Here, we present the three-dimensional structure of an A beta oligomer formed in a membrane mimicking environment, namely an A beta(1-42) tetramer, which comprises a six stranded beta-sheet core. The two faces of the beta-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of A beta(1-42) in the sample, A beta(1-42) octamers are also formed, made by two A beta(1-42) tetramers facing each other forming a beta-sandwich structure. Notably, A beta(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core beta-sheets edges of the oligomers.
12.	Diercks, Tammo, et al. (författare) qTROSY - a novel scheme for recovery of the anti-TROSY magnetisation 2005 Ingår i: JOURNAL OF BIOMOLECULAR NMR. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 32:2, s. 113-127 Tidskriftsartikel (refereegranskat)
13.	Gołowicz, D., et al. (författare) Fast time-resolved NMR with non-uniform sampling 2020 Ingår i: Progress in Nuclear Magnetic Resonance Spectroscopy. - : Elsevier BV. - 0079-6565. ; 116, s. 40-55 Tidskriftsartikel (refereegranskat)abstract NMR spectroscopy is a versatile tool for studying time-dependent processes: chemical reactions, phase transitions or macromolecular structure changes. However, time-resolved NMR is usually based on the simplest among available techniques – one-dimensional spectra serving as “snapshots” of the studied process. One of the reasons is that multidimensional experiments are very time-expensive due to costly sampling of evolution time space. In this review we summarize efforts to alleviate the problem of limited applicability of multidimensional NMR in time-resolved studies. We focus on techniques based on sparse or non-uniform sampling (NUS), which lead to experimental time reduction by omitting a significant part of the data during measurement and reconstructing it mathematically, adopting certain assumptions about the spectrum. NUS spectra are faster to acquire than conventional ones and thus better suited to the role of “snapshots”, but still suffer from non-stationarity of the signal i.e. amplitude and frequency variations within a dataset. We discuss in detail how these instabilities affect the spectra, and what are the optimal ways of sampling the non-stationary FID signal. Finally, we discuss related areas of NMR where serial experiments are exploited and how they can benefit from the same NUS-based approaches. © 2019 Elsevier B.V.
14.	Guo, Y., et al. (författare) Hypercomplex Low Rank Reconstruction for NMR Spectroscopy 2023 Ingår i: Signal Processing. - : Elsevier BV. - 0165-1684. ; 203 Tidskriftsartikel (refereegranskat)abstract Nuclear magnetic resonance (NMR) spectroscopy serves as an important tool to analyze chemicals and proteins in bioengineering. Multi-dimensional NMR offers a major improvement in resolution with multi-dimensional spectrum, but significantly increases data acquisition time and produces hypercomplex data that is difficult to be handled. To reduce this time, non-uniformly sampling can be applied to obtain undersampled data and using a reconstruction approach, such as the state-of-the-art low rank method, to remove the spectral artifacts introduced by undersampling. However, only complex format of signal, including the real and imaginary parts, is considered in previous low rank approach, which is less efficient when dealing with hypercomplex data that has multiple components. To solve this problem, a hypercomplex low rank model is proposed by introducing an adjoint matrix operation and then solved with a fast matrix factorization algorithm. This method explores redundant information among all the components of hypercomplex signal. Using simulated data and real protein data, we demonstrate that the proposed method provides a fast and high-fidelity reconstruction of hypercomplex spectroscopy in fast NMR. © 2022 Elsevier B.V.
15.	Gustavsson, Emil, 1987, et al. (författare) Modulation of Structural Heterogeneity Controls Phytochrome Photoswitching 2020 Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 118:2, s. 415-421 Tidskriftsartikel (refereegranskat)abstract Phytochromes sense red/far-red light and control many biological processes in plants, fungi, and bacteria. Although the crystal structures of dark- and light-adapted states have been determined, the molecular mechanisms underlying photoactivation remain elusive. Here, we demonstrate that the conserved tongue region of the PHY domain of a 57-kDa photosensory module of Deinococcus radiodurans phytochrome changes from a structurally heterogeneous dark state to an ordered, light-activated state. The results were obtained in solution by utilizing a laser-triggered activation approach detected on the atomic level with high-resolution protein NMR spectroscopy. The data suggest that photosignaling of phytochromes relies on careful modulation of structural heterogeneity of the PHY tongue.
16.	Gutmanas, Aleksandras, et al. (författare) Accurate relaxation parameters for large proteins. 2004 Ingår i: Journal of magnetic resonance (San Diego, Calif. : 1997). - : Elsevier BV. - 1090-7807. ; 167:1, s. 107-13 Tidskriftsartikel (refereegranskat)abstract The practical applicability, performance, and robustness of three-way decomposition (TWD) for the extraction of relaxation parameters are demonstrated for a large protein with 370 residues, the maltose binding protein. An ordinary set of seven relaxation-modulated (15)N HSQC spectra, recorded at another site, is systematically analyzed. For all 341 assigned backbone amide groups, including 21 pairs and one group of three overlapped peaks, T1 decay values were determined. On isolated peaks, TWD extracts T1 values with systematically lower error bounds compared to conventional tools, although for these simple cases the improvements remain limited. However, in the presence of spectral artifacts, the decrease in errors can become significant, demonstrating the higher robustness of TWD. For about half of the peaks in overlapped regions, the decomposition allowed separation of the signals, yielding significantly different T1 values between overlapping signals. For the rest, similarity of the decay times for the two or three overlapping signals could be confirmed within usually low error bounds. The use of TWD thus leads to a significant increase in the number of accessible relaxation probes in large proteins. With a newly implemented graphical user interface, the application of TWD requires merely a peak list, and thus no additional effort compared to conventional approaches is needed.
17.	Han, X., et al. (författare) Assignment of IVL-Methyl side chain of the ligand-free monomeric human MALT1 paracaspase-IgL(3) domain in solution 2022 Ingår i: Biomolecular Nmr Assignments. - : Springer Science and Business Media LLC. - 1874-2718 .- 1874-270X. ; 16:2, s. 363-371 Tidskriftsartikel (refereegranskat)abstract Mucosa-associated lymphoid tissue protein 1 (MALT1) plays a key role in adaptive immune responses by modulating specific intracellular signalling pathways that control the development and proliferation of both T and B cells. Dysfunction of these pathways is coupled to the progress of highly aggressive lymphoma as well as to potential development of an array of different immune disorders. In contrast to other signalling mediators, MALT1 is not only activated through the formation of the CBM complex together with the proteins CARMA1 and Bcl10, but also by acting as a protease that cleaves multiple substrates to promote lymphocyte proliferation and survival via the NF-kappa B signalling pathway. Herein, we present the partial H-1, C-13 Ile/Val/Leu-Methyl resonance assignment of the monomeric apo form of the paracaspase-IgL(3) domain of human MALT1. Our results provide a solid ground for future elucidation of both the three-dimensional structure and the dynamics of MALT1, key for adequate development of inhibitors, and a thorough molecular understanding of its function(s).
18.	Hassanieh, H., et al. (författare) Fast multi-dimensional NMR acquisition and processing using the sparse FFT 2015 Ingår i: Journal of Biomolecular Nmr. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 63:1, s. 9-19 Tidskriftsartikel (refereegranskat)abstract Increasing the dimensionality of NMR experiments strongly enhances the spectral resolution and provides invaluable direct information about atomic interactions. However, the price tag is high: long measurement times and heavy requirements on the computation power and data storage. We introduce sparse fast Fourier transform as a new method of NMR signal collection and processing, which is capable of reconstructing high quality spectra of large size and dimensionality with short measurement times, faster computations than the fast Fourier transform, and minimal storage for processing and handling of sparse spectra. The new algorithm is described and demonstrated for a 4D BEST-HNCOCA spectrum.
19.	Hiller, S., et al. (författare) Backbone and ILV side chain methyl group assignments of the integral human membrane protein VDAC-1 2009 Ingår i: Biomol NMR assignments. Tidskriftsartikel (refereegranskat)abstract The voltage dependent anion channel (VDAC) forms a channel for metabolites and nutrients in the outer membrane of mitochondria, and it is also involved in apoptotic pathways. Here, we report sequence-specific NMR assignments for the isoform 1 of human VDAC reconstituted in lauryldimethylamine oxide (LDAO) detergent micelles. The assignments were deposited in the BMRB data base with accession number 16381.
20.	Hiller, S., et al. (författare) Coupled Decomposition of Four-Dimensional NOESY Spectra 2009 Ingår i: Journal of the American Chemical Society. - 0002-7863. ; 131, s. 12970-12978 Tidskriftsartikel (refereegranskat)abstract Four-dimensional (4D) NOESY spectra provide unambiguous distance information at a resolution that cannot be achieved in fewer dimensions and thus increase the quality of biomolecular structure determination substantially. Since the degree of chemical shift degeneracy increases with protein size, the use of 4D NOESY spectra is particularly important for large proteins. The potential high resolution in 4D spectra cannot be achieved in a reasonable time with conventional acquisition routines that sample the Nyquist grid uniformly. It can, however, be obtained with nonuniform sampling of the data grid, but optimal processing of such data has not yet been established. Here we describe a processing method for a pair of sparsely sampled 4D NOESY spectra, a methyl-methyl and an amide-methyl NOESY, recorded on a perdeuterated protein with protonated isoleucine, leucine, and valine methyl groups. The coupled multidimensional decomposition (Co-MDD) of these two spectra together with a 2D template spectrum results in a substantial increase in sensitivity, evidenced by 50-100% additional cross peaks, when compared to alternative processing schemes. At the same time, Co-MDD allows the use of low sparse levels of 10-15% of the full data grid for NOESY spectra. For the 283-residue integral human membrane protein VDAC-1, which has a rotational correlation time of about 70 ns in detergent micelles, the two 4D Co-MDD NOESYs yielded a total of 366 NOEs, resulting in 139 unambiguous upper limit distance constraints for the structure calculation.
21.	Hiller, S., et al. (författare) Solution structure of the integral human membrane protein VDAC-1 in detergent micelles 2008 Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 321:5893, s. 1206-1210 Tidskriftsartikel (refereegranskat)abstract The voltage- dependent anion channel ( VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. VDAC also interacts with antiapoptotic proteins from the Bcl- 2 family, and this interaction inhibits release of apoptogenic proteins from the mitochondrion. We present the nuclear magnetic resonance ( NMR) solution structure of recombinant human VDAC- 1 reconstituted in detergent micelles. It forms a 19- stranded beta barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC- 1 can form voltage- gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC- 1 for the Bcl- 2 protein Bcl-x(L), for reduced beta-nicotinamide adenine dinucleotide, and for cholesterol. Bcl-x(L) interacts with the VDAC barrel laterally at strands 17 and 18.
22.	Huang, Y., et al. (författare) Exponential Signal Reconstruction With Deep Hankel Matrix Factorization 2022 Ingår i: IEEE Transactions on Neural Networks and Learning Systems. - 2162-237X. ; 34:9, s. 6214-26 Tidskriftsartikel (refereegranskat)abstract Exponential function is a basic form of temporal signals, and how to fast acquire this signal is one of the fundamental problems and frontiers in signal processing. To achieve this goal, partial data may be acquired but result in severe artifacts in its spectrum, which is the Fourier transform of exponentials. Thus, reliable spectrum reconstruction is highly expected in the fast data acquisition in many applications, such as chemistry, biology, and medical imaging. In this work, we propose a deep learning method whose neural network structure is designed by imitating the iterative process in the model-based state-of-the-art exponentials' reconstruction method with the low-rank Hankel matrix factorization. With the experiments on synthetic data and realistic biological magnetic resonance signals, we demonstrate that the new method yields much lower reconstruction errors and preserves the low-intensity signals much better than compared methods. IEEE
23.	Isaksson, Linnéa, et al. (författare) Highly Efficient NMR Assignment of Intrinsically Disordered Proteins: Application to B- and T Cell Receptor Domains 2013 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5 Tidskriftsartikel (refereegranskat)abstract We present an integrated approach for efficient characterization of intrinsically disordered proteins. Batch cell-free expression, fast data acquisition, automated analysis, and statistical validation with data resampling have been combined for achieving cost-effective protein expression, and rapid automated backbone assignment. The new methodology is applied for characterization of five cytosolic domains from T- and B-cell receptors in solution.
24.	Isaksson, Linnéa, et al. (författare) Signaling Mechanism of Phytochromes in Solution. 2021 Ingår i: Structure. - : Elsevier BV. - 1878-4186 .- 0969-2126. ; 29:2, s. 151-160 Tidskriftsartikel (refereegranskat)abstract Phytochrome proteins guide the red/far-red photoresponse of plants, fungi, and bacteria. Crystal structures suggest that the mechanism of signal transduction from the chromophore to the output domains involves refolding of the so-called PHY tongue. It is currently not clear how the two other notable structural features of the phytochrome superfamily, the so-called helical spine and a knot in the peptide chain, are involved in photoconversion. Here, we present solution NMR data of the complete photosensory core module from Deinococcus radiodurans. Photoswitching between the resting and the active states induces changes in amide chemical shifts, residual dipolar couplings, and relaxation dynamics. All observables indicate a photoinduced structural change in the knot region and lower part of the helical spine. This implies that a conformational signal is transduced from the chromophore to the helical spine through the PAS and GAF domains. The discovered pathway underpins functional studies of plant phytochromes and may explain photosensing by phytochromes under biological conditions.
25.	Jahangiri, Amir, 1987, et al. (författare) NMR spectrum reconstruction as a pattern recognition problem 2023 Ingår i: Journal of Magnetic Resonance. - : Elsevier BV. - 1090-7807 .- 1096-0856. ; 346 Tidskriftsartikel (refereegranskat)abstract A new deep neural network based on the WaveNet architecture (WNN) is presented, which is designed to grasp specific patterns in the NMR spectra. When trained at a fixed non-uniform sampling (NUS) schedule, the WNN benefits from pattern recognition of the corresponding point spread function (PSF) pattern produced by each spectral peak resulting in the highest quality and robust reconstruction of the NUS spectra as demonstrated in simulations and exemplified in this work on 2D 1H-15N correlation spectra of three representative globular proteins with different sizes: Ubiquitin (8.6 kDa), Azurin (14 kDa), and Malt1 (44 kDa). The pattern recognition by WNN is also demonstrated for successful virtual homodecoupling in a 2D methyl 1H-13C - HMQC spectrum of MALT1. We demonstrate using WNN that prior knowledge about the NUS schedule, which so far was not been fully exploited, can be used for designing new powerful NMR processing techniques that surpass the existing algorithmic methods.
26.	Karamanos, T. K., et al. (författare) A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity 2016 Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:19, s. 6271-6280 Tidskriftsartikel (refereegranskat)abstract The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta(2)-microglobulin (beta(2)m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone I-Trans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
27.	Kazimierczuk, Krzysztof, et al. (författare) A comparison of convex and non-convex compressed sensing applied to multidimensional NMR 2012 Ingår i: Journal of Magnetic Resonance. - : Elsevier BV. - 1090-7807. ; 223, s. 1-10 Tidskriftsartikel (refereegranskat)abstract The resolution of multidimensional NMR spectra can be severely limited when regular sampling based on the Nyquist-Shannon theorem is used. The theorem binds the sampling rate with a bandwidth of a sampled signal and thus implicitly creates a dependence between the line width and the time of experiment, often making the latter one very long. Recently, Candes et al. (2006)[25] formulated a non-linear sampling theorem that determines the required number of sampling points to be dependent mostly on the number of peaks in a spectrum and only slightly on the number of spectral points. The result was pivotal for rapid development and broad use of signal processing method called compressed sensing. In our previous work, we have introduced compressed sensing to multidimensional NMR and have shown examples of reconstruction of two-dimensional spectra. In the present paper we discuss in detail the accuracy and robustness of two compressed sensing algorithms: convex (iterative soft thresholding) and non-convex (iteratively re-weighted least squares with local l(0)-norm) in application to two- and three-dimensional datasets. We show that the latter method is in many terms more effective, which is in line with recent works on the theory of compressed sensing. We also present the comparison of both approaches with multidimensional decomposition which is one of the established methods for processing of non-linearly sampled data. (C) 2012 Elsevier Inc. All rights reserved.
28.	Kazimierczuk, Krzysztof, et al. (författare) Accelerated NMR Spectroscopy by Using Compressed Sensing 2011 Ingår i: Angewandte Chemie-International Edition. - : Wiley. - 1433-7851. ; 50:24, s. 5556-5559 Tidskriftsartikel (refereegranskat)
29.	Kazimierczuk, Krzysztof, et al. (författare) Non-uniform sampling: Post-Fourier era of NMR data collection and processing 2015 Ingår i: Magnetic Resonance in Chemistry. - : Wiley. - 0749-1581 .- 1097-458X. ; 53:11, s. 921-926 Tidskriftsartikel (refereegranskat)abstract The invention of multidimensional techniques in the 1970s revolutionized NMR, making it the general tool of structural analysis of molecules and materials. In the most straightforward approach, the signal sampling in the indirect dimensions of a multidimensional experiment is performed in the same manner as in the direct dimension, i.e. with a grid of equally spaced points. This results in lengthy experiments with a resolution often far from optimum. To circumvent this problem, numerous sparse-sampling techniques have been developed in the last three decades, including two traditionally distinct approaches: the radial sampling and non-uniform sampling. This mini review discusses the sparse signal sampling and reconstruction techniques from the point of view of an underdetermined linear algebra problem that arises when a full, equally spaced set of sampled points is replaced with sparse sampling. Additional assumptions that are introduced to solve the problem, as well as the shape of the undersampled Fourier transform operator (visualized as so-called point spread function), are shown to be the main differences between various sparse-sampling methods. Copyright © 2015 John Wiley & Sons, Ltd.
30.	Kazimierczuk, Krzysztof, et al. (författare) Resolution enhancement in NMR spectra by deconvolution with compressed sensing reconstruction 2020 Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 56, s. 14585-14588 Tidskriftsartikel (refereegranskat)abstract NMR spectroscopy is one of the basic tools for molecular structure elucidation. Unfortunately, the resolution of the spectra is often limited by inter-nuclear couplings. The existing workarounds often alleviate the problem by trading it for another deficiency, such as spectral artefacts or difficult sample preparation and, thus, are rarely used. We suggest an approach using the coupling deconvolution in the framework of compressed sensing (CS) spectra processing that leads to a major increase in resolution, sensitivity, and overall quality of NUS reconstruction. A new mathematical description of the decoupling by deconvolution explains the effects of thermal noise and reveals a relation with the underlying assumption of the CS. The gain in resolution and sensitivity for challenging molecular systems is demonstrated for the key HNCA experiment used for protein backbone assignment applied to two large proteins: intrinsically disordered 441-residue Tau and a 509-residue globular bacteriophytochrome fragment. The approach will be valuable in a multitude of chemistry applications, where NMR experiments are compromised by the homonuclear scalar coupling. This journal is
31.	Korzhnev, Dmitry M., et al. (författare) Multiple-site exchange in proteins studied with a suite of six NMR relaxation dispersion experiments: An application to the folding of a Fyn SH3 domain mutant 2005 Ingår i: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 127:44, s. 15602-15611 Tidskriftsartikel (refereegranskat)
32.	Korzhnev, Dmitry M., et al. (författare) Off-resonance R1(p) NMR studies of exchange dynamics in proteins with low spin-lock fields: An application to a fyn SH3 domain 2005 Ingår i: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 127:2, s. 713-721 Tidskriftsartikel (refereegranskat)
33.	Kubatova, Nina, et al. (författare) Rapid Biophysical Characterization and NMR Spectroscopy Structural Analysis of Small Proteins from Bacteria and Archaea 2020 Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 21:8, s. 1178-1187 Tidskriftsartikel (refereegranskat)abstract © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. Proteins encoded by small open reading frames (sORFs) have a widespread occurrence in diverse microorganisms and can be of high functional importance. However, due to annotation biases and their technically challenging direct detection, these small proteins have been overlooked for a long time and were only recently rediscovered. The currently rapidly growing number of such proteins requires efficient methods to investigate their structure–function relationship. Herein, a method is presented for fast determination of the conformational properties of small proteins. Their small size makes them perfectly amenable for solution-state NMR spectroscopy. NMR spectroscopy can provide detailed information about their conformational states (folded, partially folded, and unstructured). In the context of the priority program on small proteins funded by the German research foundation (SPP2002), 27 small proteins from 9 different bacterial and archaeal organisms have been investigated. It is found that most of these small proteins are unstructured or partially folded. Bioinformatics tools predict that some of these unstructured proteins can potentially fold upon complex formation. A protocol for fast NMR spectroscopy structure elucidation is described for the small proteins that adopt a persistently folded structure by implementation of new NMR technologies, including automated resonance assignment and nonuniform sampling in combination with targeted acquisition.
34.	Lesovoy, D. M., et al. (författare) Unambiguous Tracking of Protein Phosphorylation by Fast High-Resolution FOSY NMR** 2021 Ingår i: Angewandte Chemie-International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 60:44, s. 23540-23544 Tidskriftsartikel (refereegranskat)abstract Dysregulation of post-translational modifications (PTMs) like phosphorylation is often involved in disease. NMR may elucidate exact loci and time courses of PTMs at atomic resolution and near-physiological conditions but requires signal assignment to individual atoms. Conventional NMR methods for this base on tedious global signal assignment that may often fail, as for large intrinsically disordered proteins (IDPs). We present a sensitive, robust alternative to rapidly obtain only the local assignment near affected signals, based on FOcused SpectroscopY (FOSY) experiments using selective polarisation transfer (SPT). We prove its efficiency by identifying two phosphorylation sites of glycogen synthase kinase 3 beta (GSK3 beta) in human Tau40, an IDP of 441 residues, where the extreme spectral dispersion in FOSY revealed unprimed phosphorylation also of Ser409. FOSY may broadly benefit NMR studies of PTMs and other hotspots in IDPs, including sites involved in molecular interactions.
35.	Luan, Tu, 1973, et al. (författare) Accuracy and robustness of three-way decomposition applied to NMR data. 2005 Ingår i: Journal of magnetic resonance (San Diego, Calif. : 1997). - : Elsevier BV. - 1090-7807. ; 174:2, s. 188-99 Tidskriftsartikel (refereegranskat)abstract Three-way decomposition is a very versatile analysis tool with applications in a variety of protein NMR fields. It has been used to extract structural data from 3D NOESYs, to determine relaxation rates in large proteins, to identify ligand binding in screening for lead compounds, and to complement non-uniformly recorded (sparse) spectra. All applications so far concerned experimental data sets; it thus remains to address questions of accuracy and robustness of the method using simulated data where the correct answer is known. Systematic tests are presented for relaxation and NOESY data sets. Mixtures of real and synthetic data are used to allow control of various parameters and comparisons with correct reference data, while working with input that is as realistic as possible. The influence of the following parameters is evaluated: signal-to-noise, overlap of signals and the use of a regularization procedure within the algorithm. The main criteria used for the evaluation are accuracy and precision. It is shown that deterioration of accuracy is indicated by internal checks such as decrease of precision. Both with relaxation data and when interpreting NOESY spectra, three-way decomposition exhibits a robust behavior in situations with severe signal overlap and/or poor signal-to-noise, e.g., by avoiding false positives in the NOE shapes of NOESY decompositions. As a complement to this study, three-way decomposition is compared to other methods that achieve the same type of results.
36.	Mayzel, Maxim, et al. (författare) Measurement of protein backbone (CO)-C-13 and N-15 relaxation dispersion at high resolution 2017 Ingår i: Journal of Biomolecular NMR. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 69:1, s. 1-12 Tidskriftsartikel (refereegranskat)abstract Peak overlap in crowded regions of two-dimensional spectra prevents characterization of dynamics for many sites of interest in globular and intrinsically disordered proteins. We present new three-dimensional pulse sequences for measurement of Carr-Purcell-Meiboom-Gill relaxation dispersions at backbone nitrogen and carbonyl positions. To alleviate increase in the measurement time associated with the additional spectral dimension, we use non-uniform sampling in combination with two distinct methods of spectrum reconstruction: compressed sensing and co-processing with multi-dimensional decomposition. The new methodology was validated using disordered protein CD79A from B-cell receptor and an SH3 domain from Abp1p in exchange between its free form and bound to a peptide from the protein Ark1p. We show that, while providing much better resolution, the 3D NUS experiments give the similar accuracy and precision of the dynamic parameters to ones obtained using traditional 2D experiments. Furthermore, we show that jackknife resampling of the spectra yields robust estimates of peak intensities errors, eliminating the need for recording duplicate data points.
37.	Mayzel, Maxim, et al. (författare) The causality principle in the reconstruction of sparse NMR spectra 2014 Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345. ; 50:64, s. 8947-8950 Tidskriftsartikel (refereegranskat)abstract Non-uniform sampling offers a dramatic increase in the power and efficiency of magnetic resonance techniques in chemistry, molecular structural biology, and other fields. Here we show that use of the causality property of an NMR signal is a general approach for major reduction of measuring time and quality improvement of the sparsely detected spectra.
38.	Mayzel, Maxim, et al. (författare) Time-resolved multidimensional NMR with non-uniform sampling 2014 Ingår i: Journal of Biomolecular Nmr. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 58:2, s. 129-139 Tidskriftsartikel (refereegranskat)abstract Time-resolved experiments demand high resolution both in spectral dimensions and in time of the studied kinetic process. The latter requirement traditionally prohibits applications of the multidimensional experiments, which, although capable of providing invaluable information about structure and dynamics and almost unlimited spectral resolution, require too lengthy data collection. Our work shows that the problem has a solution in using modern methods of NMR data collection and signal processing. A continuous fast pulsing three-dimensional experiment is acquired using non-uniform sampling during full time of the studied reaction. High sensitivity and time-resolution of a few minutes is achieved by simultaneous processing of the full data set with the multi-dimensional decomposition. The method is verified and illustrated in realistic simulations and by measuring deuterium exchange rates of amide protons in ubiquitin. We applied the method for characterizing kinetics of in vitro phosphorylation of two tyrosine residues in an intrinsically disordered cytosolic domain of the B cell receptor protein CD79b. Signals of many residues including tyrosines in both phosphorylated and unmodified forms of CD79b are found in a heavily crowded region of 2D H-1-N-15 correlation spectrum and the significantly enhanced spectral resolution provided by the 3D time-resolved approach was essential for the quantitative site-specific analysis.
39.	Novel Sampling Approaches in Higher Dimensional NMR 2012 Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)
40.	Orekhov, Vladislav, 1966, et al. (författare) Analysis of non-uniformly sampled spectra with Multi-Dimensional Decomposition 2011 Ingår i: Progress in Nuclear Magnetic Resonance Spectroscopy. ; 59, s. 271-292 Forskningsöversikt (refereegranskat)
41.	Orekhov, Vladislav, 1966, et al. (författare) Data Processing Methods: Fourier and Beyond 2023 Ingår i: Two-Dimensional (2D) NMR Methods. - 9781119806721 ; , s. 19-46 Bokkapitel (refereegranskat)abstract This chapter presents a compact overview of both practical and rigorously mathematical aspects of modern NMR signal processing. It discusses the properties of the Fourier transform (FT), which will be later useful to explain the effects of the experimental imperfections and signal processing procedures. The fast FT algorithm, used to calculate the discrete FT requires the same number of points in the input and output. However, one can increase the number of spectral points to any desired value by zero filling, that is, extending the free induction decay by adding artificial data points equal to zero at the end. The quadrature detection in one-dimensional spectra is realized through the acquisition of the two modulations, interpreted as real and imaginary parts of a complex NMR signal. The Projection Theorem is a powerful tool, useful in accelerating NMR experiments of dimensionality three and more.
42.	Orekhov, Vladislav, 1966, et al. (författare) Double- and zero-quantum NMR relaxation dispersion experiments sampling millisecond time scale dynamics in proteins 2004 Ingår i: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 126:6, s. 1886-1891 Tidskriftsartikel (refereegranskat)
43.	Orekhova, Elena V, 1967, et al. (författare) Unraveling superimposed EEG rhythms with multi-dimensional decomposition. 2011 Ingår i: Journal of neuroscience methods. - : Elsevier BV. - 1872-678X .- 0165-0270. ; 195:1, s. 47-60 Tidskriftsartikel (refereegranskat)abstract Scalp-recorded EEG activity reflects a number of oscillatory phenomena, many of which are generated by coupled brain sources or behave as travelling waves. Decomposition of EEG oscillations into sets of coherent processes may help investigation of the underlying functional brain networks. Traditional decomposition methods, such as ICA and PCA, cannot satisfactorily characterize coherent EEG oscillations. Moreover, these methods impose non-physiological constraints (orthogonality, maximal time independence) on the solutions. We introduce the C(3)R-MDD method, that is based on recursive multi-dimensional decomposition (R-MDD). The method allows separation of ongoing EEG into a predefined number of coherent oscillatory processes. Applied to a multichannel complex cross-correlation array (C(3)), the method extracts oscillatory processes characterized by a dominant frequency, spatial amplitude-phase distribution, and stability in time. Introduction of an additional dimension of experimental conditions allows characterization of condition-related dynamics of the processes. In this study, we first used C(3)R-MDD to decompose a simulated signal created by superposition of components with known properties. Meaningful solutions were obtained even with a suboptimal number of components in the model. Second, we applied the method to decompose rhythmic processes in ongoing low- and high-frequency EEG records of two subjects and demonstrated good reproducibility of the components obtained with different solutions, two halves of the EEG record, and different experimental sessions. The C(3)R-MDD method is compared with other types of signal decomposition: real-numbers ICA and real-numbers MDD.
44.	Pustovalova, Y., et al. (författare) NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR 2021 Ingår i: Magnetic Resonance. - : Copernicus GmbH. - 2699-0016. ; 2:2, s. 843-861 Tidskriftsartikel (refereegranskat)abstract Although the concepts of nonuniform sampling (NUS) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago (Bodenhausen and Ernst, 1981; Barna and Laue, 1987), it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., “resolution”) or peaks of weak intensity (i.e., “sensitivity”). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the “Nonuniform Sampling Contest” (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform.
45.	Pustovalova, Yulia, et al. (författare) XLSY: Extra-Large NMR Spectroscopy. 2018 Ingår i: Angewandte Chemie (International ed. in English). - : Wiley. - 1521-3773. ; 57:43, s. 14043-14045 Tidskriftsartikel (refereegranskat)abstract NMR studies of intrinsically disordered proteins and other complex biomolecular systems require spectra with the highest resolution and dimensionality. An efficient approach, extra-large NMR spectroscopy, is presented for experimental data collection, reconstruction, and handling of very large NMR spectra by a combination of the radial and non-uniform sampling, a new processing algorithm, and rigorous statistical validation. We demonstrate the first high-quality reconstruction of a full seven-dimensional HNCOCACONH and two five-dimensional HACACONH and HN(CA)CONH experiments for a representative intrinsically disordered protein α-synuclein. XLSY will significantly enhance the NMR toolbox in challenging biomolecular studies.
46.	Qiu, Tianyu, et al. (författare) High-fidelity spectroscopy reconstruction in accelerated NMR. 2018 Ingår i: Chemical communications (Cambridge, England). - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 54:78, s. 10958-10961 Tidskriftsartikel (refereegranskat)abstract Non-uniform sampling significantly accelerates the data acquisition time in NMR spectroscopy, but spectra must be reconstructed with appropriate methods. A high-fidelity reconstruction method is proposed to preserve low-intensity spectral peaks and provide stable reconstruction under different sampling trials.
47.	Qiu, Tianyu, 1994, et al. (författare) Resolution enhancement of NMR by decoupling with the low-rank Hankel model 2023 Ingår i: Chemical Communications. - 1359-7345 .- 1364-548X. ; 59:36, s. 5475-5478 Tidskriftsartikel (refereegranskat)abstract Nuclear magnetic resonance (NMR) spectroscopy has become a formidable tool for biochemistry and medicine. Although J-coupling carries essential structural information it may also limit the spectral resolution. Homonuclear decoupling remains a challenging problem. In this work, we introduce a new approach that uses a specific coupling value as prior knowledge, and the Hankel property of the exponential NMR signal to achieve broadband heteronuclear decoupling using the low-rank method. Our results on synthetic and realistic HMQC spectra demonstrate that the proposed method not only effectively enhances resolution by decoupling, but also maintains sensitivity and suppresses spectral artefacts. The approach can be combined with non-uniform sampling, which means that the resolution can be further improved without any extra acquisition time.
48.	Qu, Xiaobo, et al. (författare) Accelerated Nuclear Magnetic Resonance Spectroscopy with Deep Learning. 2020 Ingår i: Angewandte Chemie. - : Wiley. - 1521-3773 .- 1433-7851. ; 59:26, s. 10297-10300 Tidskriftsartikel (refereegranskat)abstract Nuclear magnetic resonance (NMR) spectroscopy serves as an indispensable tool in chemistry and biology but often suffers from long experimental time. We present a proof-of-concept of application of deep learning and neural network for high-quality, reliable, and very fast NMR spectra reconstruction from limited experimental data. We show that the neural network training can be achieved using solely synthetic NMR signal, which lifts the prohibiting demand for large volume of realistic training data usually required in the deep learning approach.
49.	Qu, X. B., et al. (författare) Accelerated NMR Spectroscopy with Low-Rank Reconstruction 2015 Ingår i: Angewandte Chemie-International Edition. - : Wiley. - 1433-7851. ; 54:3, s. 852-854 Tidskriftsartikel (refereegranskat)abstract Accelerated multi-dimensional NMR spectroscopy is a prerequisite for high-throughput applications, studying short-lived molecular systems and monitoring chemical reactions in real time. Non-uniform sampling is a common approach to reduce the measurement time. Here, a new method for high-quality spectra reconstruction from non-uniformly sampled data is introduced, which is based on recent developments in the field of signal processing theory and uses the so far unexploited general property of the NMR signal, its low rank. Using experimental and simulated data, we demonstrate that the low-rank reconstruction is a viable alternative to the current state-of-the-art technique compressed sensing. In particular, the low-rank approach is good in preserving of low-intensity broad peaks, and thus increases the effective sensitivity in the reconstructed spectra.
50.	Rosenlöw, Joakim, et al. (författare) Tyrosine Phosphorylation within the Intrinsically Disordered Cytosolic Domains of the B-Cell Receptor: An NMR-Based Structural Analysis 2014 Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4 Tidskriftsartikel (refereegranskat)abstract Intrinsically disordered proteins are found extensively in cell signaling pathways where they often are targets of posttranslational modifications e. g. phosphorylation. Such modifications can sometimes induce or disrupt secondary structure elements present in the modified protein. CD79a and CD79b are membrane-spanning, signal-transducing components of the B-cell receptor. The cytosolic domains of these proteins are intrinsically disordered and each has an immunoreceptor tyrosine-based activation motif (ITAM). When an antigen binds to the receptor, conserved tyrosines located in the ITAMs are phosphorylated which initiate further downstream signaling. Here we use NMR spectroscopy to examine the secondary structure propensity of the cytosolic domains of CD79a and CD79b in vitro before and after phosphorylation. The phosphorylation patterns are identified through analysis of changes of backbone chemical shifts found for the affected tyrosines and neighboring residues. The number of the phosphorylated sites is confirmed by mass spectrometry. The secondary structure propensities are calculated using the method of intrinsic referencing, where the reference random coil chemical shifts are measured for the same protein under denaturing conditions. Our analysis revealed that CD79a and CD79b both have an overall propensity for alpha-helical structure that is greatest in the C-terminal region of the ITAM. Phosphorylation of CD79a caused a decrease in helical propensity in the C-terminal ITAM region. For CD79b, the opposite was observed and phosphorylation resulted in an increase of helical propensity in the C-terminal part.

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