Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids

Otaki, Hiroki; Taguchi, Yoshitaka; Nishida, Naoshi

doi:10.1101/326462

Cited by 7 publications

(25 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the knowledge from studies on αSyn amyloids [24][25], we attempted to model a local structure of PrP Sc with a U-shaped loop. A region comprising a glycine (Gly)-rich motif encompassing 123-127 of human PrP was suitable for a U-shaped loop and, in addition, the anti-prion effect of valine at residue 127 (V127) against various sporadic CJD [36] which is reminiscent of the destabilizing effects of V84 in αSyn amyloid supported the presence of a U-shaped loop in the region.…”

Section: Resultsmentioning

confidence: 99%

“…In in-vitro cross-seeding between ovine PrP and cervine CWD, I208M (in ovine numbering) mutation showed profound influences on seeding efficiencies [23]. Given those documented facts, we were interested in effects of different hydrophobic residues on structures of in-register parallel β-sheet amyloids, particularly whether Met has unique properties than other hydrophobic amino acids, and started the investigation with an in-register parallel β-sheet amyloid of α-synuclein (αSyn) as a surrogate structural model for PrP Sc , as we previously did [24][25].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc

Otaki

Taguchi

Nishida

2019

Preprint

Self Cite

View full text Add to dashboard Cite

17Prions are pathogens which consist solely of abnormal isoform of prion protein (PrP Sc ) without any genetic material, 18 and they therefore depend on purely protein-based mechanism for diversification and maintenance of pathogenic 19 properties/information for strain diversity that has not been fully elucidated. According to the protein-only 20 hypothesis, pathogenic properties of prions are determined by conformations of the constituent PrP Sc , and 21 alterations to even a single residue can drastically change the properties when the residue is located at a critical 22 α Syn amyloid, whereas other hydrophobic amino acids 32 destabilized it. The stabilizing effect of methionine was attributable to the long side chain without Cβ branching. 33 The local structural model of PrP Sc also revealed unique effects of hydrophobic amino acids depending on regional 34 structures. Our study demonstrated specifically how and in what structure of in-register parallel β -sheet amyloids 35 hydrophobic residues can exert unique effects and provide insights into the molecular mechanism of strain 36 diversity of prions and other pathogenic amyloids. 37 38 65 high-resolution structural analyses [11][12][13][14][15][16]. 66 Not only by the Met/Val polymorphic codon 129, strain/species barriers of prions can be caused by 67 conservative replacements between different groups of hydrophobic amino acids. In experiments with 68 C-terminally-truncated Y145Stop mutant of human PrP and the counterparts of mouse and Syrian hamster PrPs, 69 whether residue 138 or 139 (in human numbering throughout unless otherwise noted) is isoleucine (Ile) or Met was 70 critical for efficient amyloid formation and cross-seeding among them [17][18]. In transmission of prions of sporadic 71 CJD homozygous for M129 to transgenic mice expressing human-mouse chimeric PrP, I138M substitution 72 substantially extended incubation periods [19]. M109 and M112 are influential on transmission efficiencies among 73 different hamster species [20][21]. In an experiment observing influences of systematically-introduced mutations of 74 mouse PrP on conversion efficiencies in scrapie-infected Neuro2a cells, Met at some positions, e.g., M213, were 75replaceable with other hydrophobic residues like Leu, whereas unreplaceable at other residues, e.g., M206 [22]. In 76 109 positive-value areas of (Pβ-Pα) and (Pβ-Pc) in residues 88-90 disappeared, making the C-terminal region solely 110 (Pα-Pc)-positive. Those alterations in predicted propensity profiles by the mutations were consistent with high 111 α -helix propensity of Met [34][35]. 112 MD simulation of α Syn(E61M) and α Syn(G84M) 113 MD simulations of homo-oligomer amyloids of α Syn(E61M) and α Syn(G84M) revealed that both the mutations

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc

Otaki

Taguchi

Nishida

2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Detailed protocols of the modeling mutant αSyn amyloids, MD simulation, short MD simulation, and various analyses were mostly the same as described in the preprint on bioRxiv [25]. Here we briefly describe essential points.…”

Section: Methodsmentioning

confidence: 99%

“…We used the Greek-key αSyn amyloid (PDB ID: 2n0a [29]) as the starting structure, after truncating the disordered N- and C-terminal regions (residues 1–35 and 100–140, respectively) [25]. The N- and C-termini were acetylated and N -methylated using AmberTools16 [38].…”

Section: Methodsmentioning

confidence: 99%

“…Given those documented facts, we asked ourselves whether Met could have distinct properties than other hydrophobic amino acids that uniquely affect structures of PrP Sc . To address the question, we exploited an in-register parallel β-sheet amyloid of α-synuclein (αSyn) as a surrogate structural model for PrP Sc , as we previously did [24][25].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Otaki

Taguchi

Nishida

2019

Preprint

Self Cite

View full text Add to dashboard Cite

17Mechanism of strain diversity of prions is a long-standing conundrum, because prions consist solely of abnormal 18 isoform of prion protein (PrP Sc ) devoid of genetic material. Pathogenic properties of prions are determined by 19 conformations of the constituent PrP Sc according to the protein-only hypothesis, and alterations to even a single 20 residue can drastically change the properties when the residue is located at a critical position for the structure of 21 PrP Sc . Interestingly, methionine (Met) is often recognized as the polymorphic or species-specific residues 22 34 Prion diseases are a group of neurodegenerative disorders which are characterized by accumulation of the 35 abnormal isoform (PrP Sc ) of prion protein (PrP) in the central nervous system [1]. Prion diseases have three 36 etiologies, i.e., sporadic, inherited and acquired, depending on how the causative PrP Sc starts propagation in the 37 body; in sporadic and inherited prion diseases, e.g., sporadic Creutzfeldt-Jakob disease (CJD) and fatal familial 38 insomnia (FFI), respectively, the causative PrP Sc are generated by spontaneous conformational conversion of 39 endogenous normal isoform PrP into PrP Sc without or with mutation in PRNP gene, which encodes PrP. Acquired 40 prion diseases are caused by intake of exogenous PrP Sc as infectious agents, prions, e.g. epidemic bovine 41 spongiform encephalopathy (BSE) in cattle [2] and chronic wasting disease (CWD) in cervids [3]. Prions behave 42 similarly as viruses, with high infectivity, existence of many strains, species/strain barriers, and adaptation to new 43 hosts, despite the lack of conventional genetic material. These virus-like properties of prions are explained by 44 hypothesis that pathogenic properties of prions are enciphered in the conformations of PrP Sc , i.e., protein-only 45 hypothesis [1][4]. 46 Indeed, pathogenic properties of prions and the consequent clinical features are greatly affected by the 47 48 fact that conformations of proteins are determined by the primary structures. For example, in sporadic CJD, PrP 49 deposition patterns, lesion profiles in the brain, clinical presentations, and apparent molecular sizes of 50 protease-resistant cores of PrP Sc are varied depending on whether the polymorphic codon 129 is methionine (Met) 51 or valine (Val) [5]. A pathogenic mutation D178N of human PrP reportedly causes either FFI or familial CJD in 52 association with Met129 or Val129, respectively [6]. The codon 129 polymorphism also determines susceptibility to 53 prion infections, i.e., species/strain barriers: a vast majority of new-variant CJD cases which resulted from 54 trans-species transmission of BSE to humans are homozygous for Met129 [7][8]; the polymorphic codon 132 of elk 55 PrP, either Met or leucine (Leu), which is equivalent to the codon 129 polymorphism of human PrP, also affects 56 susceptibility to CWD [9][10]. From the viewpoint of the protein-only hypothesis, effects of the polymorphisms are 57 mediated by structural alterations of the constitue...

show abstract

The PyInteraph Workflow for the Study of Interaction Networks From Protein Structural Ensembles

Lambrughi

Sora

Tiberti

2020

Methods in Molecular Biology

View full text Add to dashboard Cite

Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids

Abstract: 25Diversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of 26 abnormally-folded forms of single protein species, prion protein (PrP Sc ), without genome. Although the 27

Cited by 7 publications

References 45 publications

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc

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

The PyInteraph Workflow for the Study of Interaction Networks From Protein Structural Ensembles

Contact Info

Product

Resources

About

Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids

Abstract: 25Diversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of 26 abnormally-folded forms of single protein species, prion protein (PrP Sc ), without genome. Although the 27

Cited by 7 publications

References 45 publications

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

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

The PyInteraph Workflow for the Study of Interaction Networks From Protein Structural Ensembles

Contact Info

Product

Resources

About

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrP^Sc