Biology subjects

Peak-Chew, S.

Publications and source records attributed to Peak-Chew, S..

6 recordsLinked to original sources

bioRxiv2026

Dimerisation and twist reversal of the Lewy fold in α-synuclein mutants with Parkinson's disease and dementia

Dominantly inherited missense and gene dosage mutations in SNCA, the -synuclein gene, cause familial forms of Parkinsons disease and dementia. Here we report the structures of -synuclein filaments from the brains of such individuals. Pathogenic mutations A53T and G51D in SNCA give rise to singlets and doublets of the Lewy fold with a left-handed helical twist in the absence of a peptide-like density for island A. By contrast, filaments from the non-pathogenic variant H50Q consist of singlets of the right-handed Lewy fold with a density for island A, like filaments of wild-type -synuclein. The structures of filaments from homozygous mice transgenic for human mutant A53T -synuclein (line M83) are unlike those from human brains. They are more similar to the multiple system atrophy folds than to the Lewy fold of Parkinsons disease, Parkinsons disease dementia and dementia with Lewy bodies

biophysics↗

bioRxiv2026

The Pick fold in tau filaments from human MAPT mutants

Mutations in MAPT, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Picks disease and filaments made of three-repeat tau. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from individuals with MAPT mutations D252V, G272V, S320F and {Delta}G389-I392. The two-layered Pick fold was present in the individuals with mutations D252V and {Delta}G389-I392. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272-341 rotated by 20-25{degrees} with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V or S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.

biophysics↗

bioRxiv2024

Tau filaments with the Alzheimer fold in cases with MAPT mutations V337M and R406W

Frontotemporal dementia (FTD) and Alzheimers disease are the most common forms of early-onset dementia. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.

biophysics↗

bioRxiv2023

Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy

We used electron cryo-microscopy (cryo-EM) to determine the structures of A{beta}40 filaments from the leptomeninges of individuals with Alzheimers disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 [A], we found three types of filaments. However, our new structures, solved to a resolution of 2.4 [A] resolution, revealed differences in the sequence assignment that redefine the fold of A{beta}40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of A{beta}42 and blood vessel deposits of A{beta}40 have distinct structures, supporting the view that Alzheimers disease and cerebral amyloid angiopathy are different A{beta} proteinopathies.

neuroscience↗

bioRxiv2019

Ebselen inhibits mycobacterial ESX-1 secretion through modification of EccA1

The type VII secretion system ESX-1 mediates virulence in Mycobacterium tuberculosis and Mycobacterium marinum. We find that in M. marinum, the synthetic organoselenium compound ebselen inhibits secretion of ESAT-6, a major ESX-1 substrate. We find that ebselen inhibits the in vitro activity of the ESX-1 AAA+ ATPase EccA1, which potentiates ESX-1 substrate secretion and function. Ebselen modifies a cysteine in its N-terminal tetratricopeptide repeat domain that is required for EccA1s in vitro ATPase activity. Surprisingly, mutational analyses show this this cysteine is not required for ESX-1 secretion or ebselens activity, showing that ebselen inhibits ESX-1 secretion independently of inhibiting EccA1 activity in vitro. While the mechanism by which ebselen inhibits ESX-1 secretion remains elusive, we show that it attenuates ESX-1-mediated damage of M. marinum-containing macrophage phagosomes and inhibits intramacrophage growth. Extending our studies to M. tuberculosis, we find that ebselen inhibits ESX-1 secretion and phagosomal membrane damage in this organism. This work provides insight into EccA1 biology. Ebselen is an orally active drug in clinical trials for other conditions and this work suggests its potential in tuberculosis therapy.

microbiology↗

bioRxiv2018

Covalent Aurora A regulation by the metabolic integrator coenzyme A

Aurora A is a cell cycle protein kinase implicated in multiple human cancers, and several Aurora A-specific kinase inhibitors have progressed into clinical trials. In this study, we report structural and cellular analysis of a novel biochemical mode of Aurora A inhibition, which occurs through reversible covalent interaction with the universal metabolic integrator coenzyme A (CoA). Mechanistically, the CoA 3-phospho ADP moiety interacts with Thr 217, an Aurora A selectivity filter, which permits the formation of an unprecedented covalent bond with Cys 290 in the kinase activation segment, lying some 15 [A] away. CoA modification (CoAlation) of endogenous Aurora A is rapidly induced by oxidative stresses at Cys 290 in human cells, and microinjection of CoA into mouse embryos perturbs meitoic spindle formation and chromosome alignment. Aurora A regulation by CoA reveals how targeting of Aurora A might be accomplished in the future by development of a double-anchored covalent inhibitor.

biochemistry↗