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ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization.

Abstract：

:Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

DiDonato M,Craig L,Huff ME,Thayer MM,Cardoso RM,Kassmann CJ,Lo TP,Bruns CK,Powers ET,Kelly JW,Getzoff ED,Tainer JA

doi

10.1016/s0022-2836(03)00889-1

keywords:

subject

Has Abstract

pub_date

2003-09-19 00:00:00

pages

601-15

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022283603008891

journal_volume

332

pub_type

杂志文章

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