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

Abstract

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...

Molecular Tuning of the Nano–Bio Interface: Alpha-Synuclein’s Surface Targeting with Doped Carbon Nanostructures

“…On the other hand, although the secondary structure of β-sheets is low in the α-synuclein structure, the reduction of this structure in the presence of nanoparticles indicates instability in the structure of α-synuclein and thus prevents its folding. Also, in fact, the presence of nanoparticles has caused the deformation of the MET residue, which is the cause of α-synuclein stabilization . The MET residue has a long chain that stabilizes the structure of the α-synuclein as well as the secondary structure of the β-sheets.…”

“…Also, in fact, the presence of nanoparticles has caused the deformation of the MET residue, which is the cause of αsynuclein stabilization. 34 The MET residue has a long chain that stabilizes the structure of the α-synuclein as well as the secondary structure of the β-sheets. But the use of nanostructures has caused the deformation of α-synuclein and reduced β-sheet structures due to the MET residue.…”