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Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates.

Abstract：

:Aggregation of Cu, Zn superoxide dismutase (SOD1) is often found in amyotrophic lateral sclerosis patients. The fibrillar aggregates formed by wild type and various disease-associated mutants have recently been found to have distinct cores and morphologies. Previous computational and experimental studies of wild-type SOD1 suggest that the apo-monomer, highly aggregation prone, displays substantial local unfolding dynamics. The residual folded structure of locally unfolded apoSOD1 corresponds to peptide segments forming the aggregation core as identified by a combination of proteolysis and mass spectroscopy. Therefore, we hypothesize that the destabilization of apoSOD1 caused by various mutations leads to distinct local unfolding dynamics. The partially unfolded structure, exposing the hydrophobic core and backbone hydrogen bond donors and acceptors, is prone to aggregate. The peptide segments in the residual folded structures form the "building block" for aggregation, which in turn determines the morphology of the aggregates. To test this hypothesis, we apply a multiscale simulation approach to study the aggregation of three typical SOD1 variants: wild type, G37R, and I149T. Each of these SOD1 variants has distinct peptide segments forming the core structure and features different aggregate morphologies. We perform atomistic molecular dynamics simulations to study the conformational dynamics of apoSOD1 monomer and coarse-grained molecular dynamics simulations to study the aggregation of partially unfolded SOD1 monomers. Our computational studies of monomer local unfolding and the aggregation of different SOD1 variants are consistent with experiments, supporting the hypothesis of the formation of aggregation "building blocks" via apo-monomer local unfolding as the mechanism of SOD1 fibrillar aggregation.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Ding F,Furukawa Y,Nukina N,Dokholyan NV

doi

10.1016/j.jmb.2011.12.029

subject

Has Abstract

pub_date

2012-08-24 00:00:00

pages

548-60

issue

4-5

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(11)01333-7

journal_volume

421

pub_type

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Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates.