Exposure of Hydrophobic Surfaces Initiates Aggregation of Diverse ALS-Causing Superoxide Dismutase-1 Mutants

JOURNAL OF MOLECULAR BIOLOGY

卷:399

Article

Muench, Christian¹  Bertolotti, Anne¹ 

[1] MRC, Mol Biol Lab, Cambridge CB2 0QH, England

关键词: superoxide dismutase;    amyotrophic lateral sclerosis;    aggregation;    neurodegeneration;   

DOI  :  10.1016/j.jmb.2010.04.019

来源: Elsevier

【 摘 要 】

The copper-zinc superoxide dismutase-1 (SOD1) is a highly structured protein and, a priori, one of the least likely proteins to be involved in a misfolding disease. However, more than 140, mostly missense, mutations in the SOD1 gene cause aggregation of the affected protein in familial forms of amyotrophic lateral sclerosis (ALS). The remarkable diversity of the effects of these mutations on SOD1 properties has suggested that they promote aggregation by a variety of mechanisms. Experimental assessment of surface hydrophobicity using a sensitive fluorescent-based assay, revealed that diverse ALS-causing mutations provoke SOD1 aggregation by increasing their propensity to expose hydrophobic surfaces. These findings could not be anticipated from analysis of the amino acid sequence. Our results uncover the biochemical nature of the misfolded aggregation-prone intermediate and reconcile the seemingly diverse effects of ALS-causing mutations into a unifying mechanism. Furthermore, the method we describe here will be useful for investigating and interfering with aggregation of various proteins and thereby provide insight into the molecular mechanisms underlying many neurodegenerative diseases. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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