| 1. |
- Abelein, Axel, et al.
(author)
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The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway
- 2014
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In: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 19:4-5, s. 623-634
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Research review (peer-reviewed)abstract
- The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.
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| 2. |
- Bartelink, Eric J., et al.
(author)
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A Case of Contested Cremains Analyzed Through Metric and Chemical Comparison
- 2015
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In: Journal of Forensic Sciences. - : Wiley. - 0022-1198 .- 1556-4029. ; 60:4, s. 1068-1073
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Journal article (peer-reviewed)abstract
- Since the 1980s, cremation has become the fastest growing area of the U.S. funeral industry. At the same time, the number of litigations against funeral homes and cremation facilities has increased. Forensic anthropologists are often asked to determine whether the contents of an urn are actually cremated bone, and to address questions regarding the identity of the remains. This study uses both metric and chemical analyses for resolving a case of contested cremains. A cremains weight of 2021.8 g was predicted based on the decedent's reported stature and weight. However, the urn contents weighed 4173.5 g. The urn contents also contained material inconsistent with cremains (e.g., moist sediment, stones, ferrous metal). Analysis using XRD and SEM demonstrated that the urn contained thermally altered bone as well as inorganic material consistent with glass fiber cement. Although forensically challenging, cremains cases such as this one can be resolved using a multidisciplinary approach.
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| 3. |
- Berntsson, Elina, et al.
(author)
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Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4 : Similar Binding Affinities but Different Structure Induction Effects
- 2022
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In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 7:33, s. 28924-28931
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Journal article (peer-reviewed)abstract
- Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with KD values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil–coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.
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| 4. |
- Berntsson, Elina, et al.
(author)
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Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
- 2023
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods-mainly spectroscopy and imaging techniques-to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1-40), Aβ(1-40)(H6A, H13A, H14A), Aβ(4-40), and Aβ(1-42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.
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| 5. |
- Biswas, Abhijit, et al.
(author)
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Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery
- 2023
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 15:2
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Journal article (peer-reviewed)abstract
- Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.
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| 6. |
- Bulut, Ozgur, et al.
(author)
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Sexual dimorphism in frontal bone roundness quantified by a novel 3D-based and landmark-free method
- 2016
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In: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 261, s. 162.e1-162.e5
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Journal article (peer-reviewed)abstract
- In this study we present a novel and landmark-free method for quantifying shape differences between male and female frontal bones. CT scans were recorded for 80 male and 80 female Turkish hospital patients, age 25-40. The frontal bones were first isolated from the 3D models by digital cutting along the bordering sutures, and then aligned to a CAD-based sphere. This allowed us to quantify the amount of frontal bone overlapping with the sphere (on average 43.2 +/- 6.5% for males and 33.9 +/- 6.6% for females, the difference is significant at p < 0.0001), and to identify areas of shape difference and deviation from the sphere surface in male and female bones. The larger proportion of spherical frontal bone surface in males challenges the common description of the female forehead as rounder''. Based on the overlap data, we developed discriminant functions able to correctly classify 77.5% of the frontal bone models as male/female. This demonstrates that 3D-based and landmark-free approaches to statistical shape analysis may become a viable alternative to the currently dominating landmark-based approaches for shape investigation.
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| 7. |
- Carvalho, Alexandra T. P., et al.
(author)
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Understanding the structural and dynamic consequences of DNA epigenetic modifications : Computational insights into cytosine methylation and hydroxymethylation
- 2014
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In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 9:12, s. 1604-1612
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Journal article (peer-reviewed)abstract
- We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.
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| 8. |
- Chemerovski-Glikman, Marina, et al.
(author)
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Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity : In Vitro and Mechanistic Studies
- 2016
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 22:40, s. 14236-14246
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Journal article (peer-reviewed)abstract
- Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic D,L-alpha-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated alpha-synuclein (alpha-syn) aggregation to toxic oligomers by an, off-pathway mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-beta component region of alpha-syn, which are responsible for alpha-syn's membrane intercalation and self-assembly, thus changing the overall conformation of alpha-syn. CP-2 also remodels alpha-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular alpha-syn in neuronal cells overexpressing alpha-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.
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| 9. |
- Dong, Xiaolin, et al.
(author)
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Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)
- 2019
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 510:4, s. 520-524
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Journal article (peer-reviewed)abstract
- Dysregulation and aggregation of the peptide hormone IAPP (islet amyloid polypeptide, a.k.a. amylin) into soluble oligomers that appear to be cell-toxic is a known aspect of diabetes mellitus (DM) Type 2 pathology. IAPP aggregation is influenced by several factors including interactions with metal ions such as Cu(II). Because Cu(II) ions are redox-active they may contribute to metal-catalyzed formation of oxidative tyrosyl radicals, which can generate dityrosine cross-links. Here, we show that such a process, which involves Cu(II) ions bound to the IAPP peptide together with H2O2, can induce formation of large amounts of IAPP dimers connected by covalent dityrosine cross-links. This cross-linking is less pronounced at low pH and for murine IAPP, likely due to less efficient Cu(II) binding. Whether IAPP can carry out its hormonal function as a cross-linked dimer is unknown. As dityrosine concentrations are higher in blood plasma of DM Type 2 patients - arguably due to disease-related oxidative stress - and as dimer formation is the first step in protein aggregation, generation of dityrosine-linked dimers may be an important factor in IAPP aggregation and thus relevant for DM Type 2 progression.
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| 10. |
- Frković, Vedran, et al.
(author)
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Finger width as a measure of femoral block puncture site : an ultrasonographic anatomical-anthropometric study
- 2015
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In: Journal of clinical anesthesia. - : Elsevier BV. - 0952-8180 .- 1873-4529. ; 27:7, s. 553-557
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Journal article (peer-reviewed)abstract
- Study objective: Femoral nerve blockade is a regional anesthetic procedure that may be used in prehospital and emergency settings in cases of femoral trauma. Its speed and performance depend on how well the puncture site can be accurately located, something that usually is achieved via visible landmarks and/or by combining various universal preestablished measurements. Most of these methods have been derived from cadaver studies, which often suffer limitations in clinical settings. To facilitate a quick and easy determination of the puncture site, we here attempt to find an in vivo anthropometric measure that closely corresponds to the distance between the femoral artery and femoral nerve.Design: This is a prospective observational study.Patients: The study includes 67 patients presenting for elective surgery.Measurements: The distance from the femoral nerve to the femoral artery, projected to the skin, was measured by a 13-MHz ultrasonographic linear probe. Anthropometric measurements of the width of the hand fingers were carried out at the distal interphalangeal joints.Results: The distance from the femoral artery to the femoral nerve projected to the skin was found to closely correspond to the width of the fifth finger of the dominant hand measured at the distal interphalangeal joint.Conclusion: Because it relies on individual anthropometric information, this finding offers an individualized approach to determining the puncture site in a given patient. We believe that such an approach can improve and simplify femoral nerve blockade procedures in prehospital and emergency settings.
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