| 61. |
- Hatos, Andras, et al.
(författare)
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DisProt : intrinsic protein disorder annotation in 2020
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:D1, s. D269-D276
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Tidskriftsartikel (refereegranskat)abstract
- The Database of Protein Disorder (DisProt, URL:https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the 'dark' proteome.
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| 62. |
- Hayat, Sikander, et al.
(författare)
-
All-atom 3D structure prediction of transmembrane beta-barrel proteins from sequences
- 2015
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:17, s. 5413-5418
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Tidskriftsartikel (refereegranskat)abstract
- Transmembrane beta-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and alpha-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting beta-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent beta-strands at an accuracy of similar to 70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand-strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of beta-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.
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| 63. |
- Hayat, Sikander, et al.
(författare)
-
BOCTOPUS : improved topology prediction of transmembrane β barrel proteins.
- 2012
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Ingår i: Bioinformatics. - : Oxford University Press. - 1460-2059 .- 1367-4811 .- 1367-4803. ; 28:4, s. 516-522
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Transmembrane β barrel proteins (TMBs) are found in the outer membrane of Gram-negative bacteria, chloroplast and mitochondria. They play a major role in the translocation machinery, pore formation, membrane anchoring and ion exchange. TMBs are also promising targets for antimicrobial drugs and vaccines. Given the difficulty in membrane protein structure determination, computational methods to identify TMBs and predict the topology of TMBs are important.RESULTS: Here, we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). The SVMs and HMMs account for local and global residue preferences, respectively. Based on a 10-fold cross-validation test, BOCTOPUS performs better than all existing methods, reaching a Q3 accuracy of 87%. Further, BOCTOPUS predicted the correct number of strands for 83% proteins in the dataset. BOCTOPUS might also help in reliable identification of TMBs by using it as an additional filter to methods specialized in this task.AVAILABILITY: BOCTOPUS is freely available as a web server at: http://boctopus.cbr.su.se/. The datasets used for training and evaluations are also available from this site.
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| 64. |
- Hayat, Sikander, et al.
(författare)
-
Inclusion of dyad-repeat pattern improves topology prediction of transmembrane beta-barrel proteins
- 2016
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 32:10, s. 1571-1573
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate topology prediction of transmembrane beta-barrels is still an open question. Here, we present BOCTOPUS2, an improved topology prediction method for transmembrane beta-barrels that can also identify the barrel domain, predict the topology and identify the orientation of residues in transmembrane beta-strands. The major novelty of BOCTOPUS2 is the use of the dyad-repeat pattern of lipid and pore facing residues observed in transmembrane beta-barrels. In a cross-validation test on a benchmark set of 42 proteins, BOCTOPUS2 predicts the correct topology in 69% of the proteins, an improvement of more than 10% over the best earlier method (BOCTOPUS) and in addition, it produces significantly fewer erroneous predictions on non-transmembrane beta-barrel proteins.
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| 65. |
- Hayat, Sikander, et al.
(författare)
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Ranking models of transmembrane beta-barrel proteins using Z-coordinate predictions
- 2012
-
Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 28:12, s. i90-I96
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Transmembrane beta-barrels exist in the outer membrane of gram-negative bacteria as well as in chloroplast and mitochondria. They are often involved in transport processes and are promising antimicrobial drug targets. Structures of only a few beta-barrel protein families are known. Therefore, a method that could automatically generate such models would be valuable. The symmetrical arrangement of the barrels suggests that an approach based on idealized geometries may be successful. Results: Here, we present tobmodel; a method for generating 3D models of beta-barrel transmembrane proteins. First, alternative topologies are obtained from the BOCTOPUS topology predictor. Thereafter, several 3D models are constructed by using different angles of the beta-sheets. Finally, the best model is selected based on agreement with a novel predictor, ZPRED3, which predicts the distance from the center of the membrane for each residue, i.e. the Z-coordinate. The Z-coordinate prediction has an average error of 1.61 A. Tobmodel predicts the correct topology for 75% of the proteins in the dataset which is a slight improvement over BOCTOPUS alone. More importantly, however, tobmodel provides a C alpha template with an average RMSD of 7.24 A from the native structure.
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| 66. |
- Hedin, Linnea E., et al.
(författare)
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An Introduction to Membrane Proteins
- 2011
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 10:8, s. 3324-3331
-
Tidskriftsartikel (refereegranskat)abstract
- alpha-Helical membrane proteins are important for many biological functions. Due to physicochemical constraints, the structures of membrane proteins differ from the structure of soluble proteins. Historically, membrane protein structures were assumed to be more or less two-dimensional, consisting of long, straight, membrane-spanning parallel helices packed against each other. However, during the past decade, a number of the new membrane protein structures cast doubt on this notion. Today, it is evident that the structures of many membrane proteins are equally complex as for many soluble proteins. Here, we review this development and discuss the consequences for our understanding of membrane protein biogenesis, folding, evolution, and bioinformatics.
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| 67. |
- Hedin, Linnea E, 1981-
(författare)
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Intra- and intermolecular interactions in proteins : Studies of marginally hydrophobic transmembrane alpha-helices and protein-protein interactions.
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most of the processes in a living cell are carried out by proteins. Depending on the needs of the cell, different proteins will interact and form the molecular machines demanded for the moment. A subset of proteins called integral membrane proteins are responsible for the interchange of matter and information across the biological membrane, the lipid bilayer enveloping and defining the cell. Most of these proteins are co-translationally integrated into the membrane by the Sec translocation machinery. This thesis addresses two questions that have emerged during the last decade. The first concerns membrane proteins: a number of α-helices have been observed to span the membrane in the obtained three-dimensional structures even though these helices are predicted not to be hydrophobic enough to be recognized by the translocon for integration. We show for a number of these marginally hydrophobic protein segments that they indeed do not insert well outside of their native context, but that their local sequence context can improve the level of integration mediated by the translocon. We also find that many of these helices are overlapped by more hydrophobic segments. We propose, supported by experimental results, that the latter are initially integrated into the membrane, followed by post-translational structural rearrangements. Finally, we investigate whether the integration of the marginally hydrophobic TMHs of the lactose permease of Escherichia coli is facilitated by the formation of hairpin structures. However our combined efforts of computational simulations and experimental investigations find no evidence for this. The second question addressed in this thesis is that of the interpretation of the large datasets on which proteins that interact with each other in a cell. We have analyzed the results from several large-scale investigations concerning protein interactions in yeast and draw conclusions regarding the biases, strengths and weaknesses of these datasets and the methods used to obtain them.
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| 68. |
- Hedin, Linnea E., et al.
(författare)
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Membrane Insertion of Marginally Hydrophobic Transmembrane Helices Depends on Sequence Context
- 2010
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 396:1, s. 221-229
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Tidskriftsartikel (refereegranskat)abstract
- In mammalian cells, most integral membrane proteins are initially inserted into the endoplasmic reticulum membrane by the so-called Sec61 translocon. However, recent predictions suggest that many transmembrane helices (TMHs) in multispanning membrane proteins are not sufficiently hydrophobic to be recognized as such by the translocon. In this study, we have screened 16 marginally hydrophobic TMHs from membrane proteins of known three-dimensional structure. Indeed, most of these TMHs do not insert efficiently into the endoplasmic reticulum membrane by themselves. To test if loops or TMHs immediately upstream or downstream of a marginally hydrophobic helix might influence the insertion efficiency, insertion of marginally hydrophobic helices was also studied in the presence of their neighboring loops and helices. The results show that flanking loops and nearest-neighbor TMHs are sufficient to ensure the insertion of many marginally hydrophobic helices. However, for at least two of the marginally hydrophobic helices, the local interactions are not enough, indicating that post-insertional rearrangements are involved in the folding of these proteins.
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| 69. |
- Hennerdal, Aron, 1981-
(författare)
-
Application of membrane protein topology prediction
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Membrane proteins often have essential functions in the cell and many are important drug targets, yet only a small fraction of available protein structures are of membrane proteins. Experimental techniques for elucidating membrane protein structures have proven laborious and expensive, opening the field for comparatively inexpensive computational modeling. Topology prediction addresses a sub-problem of structure prediction for α-helical membrane proteins by modeling which parts of the peptide chain are in, and which parts are on either side, of the membrane. This work describes an algorithm for combining the results of several topology prediction methods to increase prediction accuracy and to quantify prediction reliability, and a faster implementation of the algorithm applicable to large-scale genome data. Further, topology prediction is applied, together with other sequence-based methods, to detect duplications in membrane proteins in whole genomes. We find more duplications in the genomes of yeast and E. coli than in human, possibly due to the abundance of nonduplicated GPCRs in human. A gene duplication and subsequent fusion event constitute a likely origin for duplicated proteins, yet only for one superfamily, the AcrB Multidrug Efflux Pump, do we find the duplicated unit in its nonduplicated form. This apparent scarcity of nonduplicated forms is confirmed when extending the study to the whole human genome. Finally, a benchmark study of topology prediction on several comparably large datasets is described. We confirm previous results showing that methods utilizing homology information top the ranking of topology prediction methods. We also see that the separation of membrane proteins from non-membrane proteins has a partially different set of requirements than topology prediction of membrane proteins, and we suggest a pipeline using different methods for these two tasks.
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| 70. |
- Hennerdal, Aron, et al.
(författare)
-
Internal duplications in alpha-helical membrane protein topologies are common but the nonduplicated forms are rare
- 2010
-
Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2305-2318
-
Tidskriftsartikel (refereegranskat)abstract
- Many alpha-helical membrane proteins contain internal symmetries, indicating that they might have evolved through a gene duplication and fusion event Here, we have characterized internal duplications among membrane proteins of known structure and in three complete genomes We found that the majority of large transmembrane (TM) proteins contain an internal duplication The duplications found showed a large variability both in the number of TM-segments included and in their orientation Surprisingly, an approximately equal number of antiparallel duplications and parallel duplications were found However, of all 11 superfamilies with an internal duplication, only for one, the AcrB Multidrug Efflux Pump, the duplicated unit could be found in its nonduplicated form An evolutionary analysis of the AcrB homologs indicates that several independent fusions have occurred, including the fusion of the SecD and SecF proteins into the 12-TM-protein SecDF in Brucella and Staphylococcus aureus In one additional case, the Vitamin B-12 transporter-like ABC transporters, the protein had undergone an additional fusion to form protein with 20 TM-helices in several bacterial genomes Finally, homologs to all human membrane proteins were used to detect the presence of duplicated and nonduplicated proteins This confirmed that only in rare cases can homologs with different duplication status be found, although internal symmetry is frequent among these proteins One possible explanation is that it is frequent that duplication and fusion events happen simultaneously and that there is almost always a strong selective advantage for the fused form
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