Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants

doi:10.1073/pnas.0501957102

Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants

Departments of ^†Biochemistry and ^§Clinical Neuroscience, Umeå University, S-901 87 Umeå, Sweden

Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved May 18, 2005 (received for review March 9, 2005)

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative syndrome associated with 114 mutations in the gene encoding the cytosolic homodimeric enzyme Cu/Zn superoxide dismutase (SOD). In this article, we report that amyotrophic lateral sclerosis-associated SOD mutations with distinctly different disease progression can be rationalized in terms of their folding patterns. The mutations are found to perturb the protein in multiple ways; they destabilize the precursor monomers (class 1), weaken the dimer interface (class 2), or both at the same time (class 1 + 2). A shared feature of the mutational perturbations is a shift of the folding equilibrium toward poorly structured SOD monomers. We observed a link, coupled to the altered folding patterns, between protein stability, net charge, and survival time for the patients carrying the mutations.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: mikael.oliveberg{at}chem.umu.se.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ALS, amyotrophic lateral sclerosis; SOD, superoxide dismutase.