scholarly journals In silico evidence of unique behaviors of methionine in an in-register parallel beta-sheet amyloid, suggestive of its possible contribution to strain diversity of amyloids

2019 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida
Keyword(s):  
Md Simulation ◽  
Genetic Material ◽  
Side Chain ◽  
Critical Position ◽  
Local Structures ◽  
Strain Diversity ◽  
Hydrophobic Amino Acids ◽  
Α Helix ◽  
Species Specific ◽  
Β Sheet

AbstractMechanism of strain diversity of prions is a long-standing conundrum, because prions consist solely of abnormal isoform of prion protein (PrPSc) devoid of genetic material. Pathogenic properties of prions are determined by conformations of the constituent PrPScaccording to the protein-only hypothesis, and alterations to even a single residue can drastically change the properties when the residue is located at a critical position for the structure of PrPSc. Interestingly, methionine (Met) is often recognized as the polymorphic or species-specific residues responsible for species/strain barriers of prions, implying its unique influences on the structures of PrPSc. However, how it is unique is difficult to demonstrate due to lack of the detailed structures of PrPSc. Here we analyzed influences of Met substitutions on structures of an in-register parallel β-sheet amyloid of α-synuclein (αSyn) by molecular dynamics (MD) simulation, to extrapolate the results to PrPSc. The MD simulation revealed that Met uniquely stabilized a U-shaped β-arch of the Greek-key αSyn amyloid, whereas other hydrophobic amino acids tended to destabilize it. The stabilizing effect of Met was attributable to the long side chain without Cβ branching. Our findings exemplify specifically how and in what structure of an in-register parallel β-sheet amyloid Met can uniquely behave, and are suggestive of its influences on structures of PrPScand strain diversity of prions. We also discuss about relations between α-helix propensity and local structures of in-register parallel amyloids.

scholarly journals Conformational Tuning of Amylin by Charged SMA Copolymers

2020 ◽  
Author(s):  
Bikash R. Sahoo ◽  
Christopher L. Souders ◽  
Magdalena Ivanova ◽  
Zhou Deng ◽  
Takahiro W. Nakayama ◽  
...  
Keyword(s):  
High Speed ◽  
Md Simulation ◽  
De Novo ◽  
2D Nmr ◽  
Charge Interaction ◽  
Α Helix ◽  
Human Amylin ◽  
Fundamental Forces ◽  
Β Sheet

AbstractHuman amylin is linked to type-2 diabetes and forms structurally heterogeneous amyloids that are pathologically relevant. Therefore, understanding the fundamental forces governing the formation of heterogeneous aggregates is important. Here, using derivatives (SMAQA+/SMAEA−) of styrene-maleic-acid (SMA) copolymer (∼2.2kDa), we demonstrate the quick formation (∼ in minutes) of amylin globulomers and fibers. High-speed AFM tracked the quick formation of de novo globular amylin oligomers and arrestment of fibrillation by SMAQA, whereas SMAEA accelerates amylin fibrillation. This observation is further supported by DOSY and STD NMR experiments. CD results show that SMAQA or SMAEA binding generates α-helix or β-sheet rich amylin structures, respectively. Atomistic insights are revealed by 2D NMR and microseconds all-atom MD simulation. Together, this study highlights the importance of charge-charge interaction in tuning the fibrillation pathways of amylin that could be of therapeutic interest.Graphical abstract

scholarly journals PrPSc-induced conformational changes and strain-specific structures of PrPSc revealed by Disulfide-crosslink scanning

2017 ◽  
Author(s):  
Yuzuru Taguchi ◽  
Noriyuki Nishida ◽  
Hermann S. Schatzl
Keyword(s):  
Conformational Changes ◽  
Genetic Material ◽  
Distal Region ◽  
Prion Strain ◽  
Local Structures ◽  
Prion Strains ◽  
Previous Hypothesis ◽  
Structural Details ◽  
Cysteine Scanning ◽  
Α Helix

ABSTRACTThere exist many phenotypically-varied prion strains, like viruses, despite the absence of conventional genetic material which codes the phenotypic information. As prion is composed solely of the pathological isoform (PrPSc) of prion protein (PrP), the strain-specific traits are hypothesized to be enciphered in the structural details of PrPSc. Identification of the structures of PrPSc is therefore vital for the understanding of prion biology, though they remain unidentified due to the incompatibility of PrPSc with conventional high-resolution structural analyses. Based on our previous hypothesis that the region between the first and the second α-helix (H1∼H2) and the distal region of the third helix (Ctrm) of the cellular isoform of PrP (PrPC) have important roles for efficient interactions with PrPSc, we created series of mutant PrPs with two cysteine substitutions (C;C-PrP) which were systematically designed to form an intramolecular disulfide crosslink between H1∼H2 and Ctrm and assessed their conformational changes by prions: Specifically, a cysteine substitution in H1∼H2 from 165 to 169 was combined with cysteine-scanning along Ctrm from 220 to 229. C;C-PrPs with the crosslinks were expressed normally with the similar glycosylation patterns and subcellular localization as the wild-type PrP albeit with varied expression levels. Interestingly, some of the C;C-PrPs converted to the protease-resistant isoforms in the N2a cells persistently infected with 22L prion strain, whereas the same mutants did not convert in the cells infected with another prion strain Fukuoka1, indicating that local structures of PrPSc in these regions vary among prion strains and contribute to prion-strain diversity. Moreover, patterns of the crosslinks of the convertible C;C-PrPs implied drastic changes in positional relations of H1∼H2 and Ctrm in the PrPSc-induced conformational changes by 22L prion. Thus, disulfide-crosslink scanning is a useful approach for investigation of strain-specific structures of PrPSc, and would be applicable to other types of amyloids as well.

scholarly journals Mechanisms of Strain Diversity of Disease-Associated in-Register Parallel β-Sheet Amyloids and Implications About Prion Strains

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 110 ◽  
Author(s):  
Yuzuru Taguchi ◽  
Hiroki Otaki ◽  
Noriyuki Nishida
Keyword(s):  
Electron Microscopy ◽  
Resonance Spectroscopy ◽  
Post Translational Modifications ◽  
Prion Strain ◽  
Local Structures ◽  
Strain Diversity ◽  
Cryo Electron Microscopy ◽  
Prion Strains ◽  
Dynamics Simulations ◽  
Β Sheet

The mechanism of prion strain diversity remains unsolved. Investigation of inheritance and diversification of protein-based pathogenic information demands the identification of the detailed structures of abnormal isoforms of the prion protein (PrPSc); however, achieving purification is difficult without affecting infectivity. Similar prion-like properties are recognized also in other disease-associated in-register parallel β-sheet amyloids including Tau and α-synuclein (αSyn) amyloids. Investigations into structures of those amyloids via solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances due to their relatively small sizes and lack of post-translational modifications. Herein, we review advances regarding pathogenic amyloids, particularly Tau and αSyn, and discuss implications about strain diversity mechanisms of prion/PrPSc from the perspective that PrPSc is an in-register parallel β-sheet amyloid. Additionally, we present our recent data of molecular dynamics simulations of αSyn amyloid, which suggest significance of compatibility between β-sheet propensities of the substrate and local structures of the template for stability of amyloid structures. Detailed structures of αSyn and Tau amyloids are excellent models of pathogenic amyloids, including PrPSc, to elucidate strain diversity and pathogenic mechanisms.

scholarly journals Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains

2018 ◽  
Author(s):  
Yuzuru Taguchi ◽  
Hiroki Otaki ◽  
Noriyuki Nishida
Keyword(s):  
Electron Microscopy ◽  
The Other ◽  
Resonance Spectroscopy ◽  
Post Translational Modifications ◽  
Local Structures ◽  
Strain Diversity ◽  
Cryo Electron Microscopy ◽  
Prion Strains ◽  
Dynamics Simulations ◽  
Β Sheet

AbstractThe mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal isoform of prion protein (PrPSc), while it is difficult to purify for analysis without affecting the infectious nature. On the other hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel β-sheet amyloids including Tau and α-synuclein (αSyn) amyloids. Investigations into structures of those amyloids by solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, particularly Tau and αSyn, and discuss their implications about strain diversity mechanisms of prion/PrPSc from the viewpoint that PrPSc is an in-register parallel β-sheet amyloid. We also present our recent data of molecular dynamics simulations of αSyn amyloid, which suggest significance of compatibility between β-sheet propensities of the substrate and local structures of the template for stability of the amyloid structures. Detailed structures of the αSyn and Tau amyloids are good surrogate models of pathogenic amyloids including PrPSc to elucidate not only the strain diversity but also their pathogenic mechanisms.

Scorpion toxin-potassium channel interaction law and its applications.

2020 ◽  
Vol 01 ◽  
Author(s):  
Zheng Zuo ◽  
Zongyun Chen ◽  
Zhijian Cao ◽  
Wenxin Li ◽  
Yingliang Wu
Keyword(s):  
Potassium Channel ◽  
Scorpion Toxin ◽  
Scorpion Toxins ◽  
Toxin Binding ◽  
Channel Interaction ◽  
Binding Interface ◽  
Α Helix ◽  
Interaction Law ◽  
Binding Interfaces ◽  
Β Sheet

: The scorpion toxins are the largest potassium channel-blocking peptide family. The understanding of toxin binding interfaces is usually restricted by two classical binding interfaces: one is the toxin α-helix motif, the other is the antiparallel β-sheet motif. In this review, such traditional knowledge was updated by another two different binding interfaces: one is BmKTX toxin using the turn motif between the α-helix and antiparallel β-sheet domains as the binding interface, the other is Ts toxin using turn motif between the β-sheet in the N-terminal and α-helix domains as the binding interface. Their interaction analysis indicated that the scarce negatively charged residues in the scorpion toxins played a critical role in orientating the toxin binding interface. In view of the toxin negatively charged amino acids as “binding interface regulator”, the law of scorpion toxin-potassium channel interaction was proposed, that is, the polymorphism of negatively charged residue distribution determines the diversity of toxin binding interfaces. Such law was used to develop scorpion toxin-potassium channel recognition control technique. According to this technique, three Kv1.3 channel-targeted peptides, using BmKTX as the template, were designed with the distinct binding interfaces from that of BmKTX through modulating the distribution of toxin negatively charged residues. In view of the potassium channel as the common targets of different animal toxins, the proposed law was also shown to helpfully orientate the binding interfaces of other animal toxins. Clearly, the toxin-potassium channel interaction law would strongly accelerate the research and development of different potassium channelblocking animal toxins in the future.

13C nuclear magnetic resonance study of cyclodipeptides containing 13C enriched hydrophobic amino acids

1980 ◽  
Vol 45 (2) ◽  
pp. 482-490 ◽  
Author(s):  
Jaroslav Vičar ◽  
François Piriou ◽  
Pierre Fromageot ◽  
Karel Bláha ◽  
Serge Fermandjian
Keyword(s):  
Amino Acids ◽  
Nuclear Magnetic Resonance ◽  
Nuclear Magnetic Resonance Study ◽  
Coupling Constants ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Magnetic Resonance Study ◽  
Side Chain Conformation ◽  
13C Nuclear Magnetic Resonance ◽  
Hydrophobic Amino Acids

The diastereoisomeric pairs of cyclodipeptides cis- and trans-cyclo(Ala-Ala), cyclo(Ala-Phe), cyclo(Val-Val) and cyclo(Leu-Leu) containing 85% 13C enriched amino-acid residues were synthesized and their 13C-13C coupling constants were measured. The combination of 13C-13C and 1H-1H coupling constants enabled to estimate unequivocally the side chain conformation of the valine and leucine residues.

scholarly journals Nanostructure of bioactive glass affects bone cell attachment via protein restructuring upon adsorption

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ukrit Thamma ◽  
Tia J. Kowal ◽  
Matthias M. Falk ◽  
Himanshu Jain
Keyword(s):  
Bioactive Glass ◽  
Cell Response ◽  
Interfacial Layer ◽  
Cell Attachment ◽  
Bone Cell ◽  
Nano Structure ◽  
Rgd Sequence ◽  
Engineered Tissue ◽  
Α Helix ◽  
Β Sheet

AbstractThe nanostructure of engineered bioscaffolds has a profound impact on cell response, yet its understanding remains incomplete as cells interact with a highly complex interfacial layer rather than the material itself. For bioactive glass scaffolds, this layer comprises of silica gel, hydroxyapatite (HA)/carbonated hydroxyapatite (CHA), and absorbed proteins—all in varying micro/nano structure, composition, and concentration. Here, we examined the response of MC3T3-E1 pre-osteoblast cells to 30 mol% CaO–70 mol% SiO2 porous bioactive glass monoliths that differed only in nanopore size (6–44 nm) yet resulted in the formation of HA/CHA layers with significantly different microstructures. We report that cell response, as quantified by cell attachment and morphology, does not correlate with nanopore size, nor HA/CHO layer micro/nano morphology, or absorbed protein amount (bovine serum albumin, BSA), but with BSA’s secondary conformation as indicated by its β-sheet/α-helix ratio. Our results suggest that the β-sheet structure in BSA interacts electrostatically with the HA/CHA interfacial layer and activates the RGD sequence of absorbed adhesion proteins, such as fibronectin and vitronectin, thus significantly enhancing the attachment of cells. These findings provide new insight into the interaction of cells with the scaffolds’ interfacial layer, which is vital for the continued development of engineered tissue scaffolds.

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