Work

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Year: 2002

Type: article

Abstract: More than 100 point mutations of the superoxide scavenger Cu/Zn superoxide dismutase (SOD; EC ) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for folding-related defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.262527099

Authors: Mikael J. Lindberg, Lena Tibell, Mikael Oliveberg

Institution: Umeå University

Language: English

Topic: Amyotrophic Lateral Sclerosis Research

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funder: Vetenskapsrådet