2v0a

From Proteopedia

Revision as of 18:14, 18 December 2007

ATOMIC RESOLUTION CRYSTAL STRUCTURE OF HUMAN SUPEROXIDE DISMUTASE

Overview

Mutations of the gene encoding Cu-Zn superoxide dismutase (SOD1) cause 20%, of the familial cases of the progressive neurodegenerative disease ALS. A, growing body of evidence suggests that in familial ALS (FALS) it is the, molecular behavior of the metal-depleted SOD1 dimer that leads to a gain, of toxic properties by misfolding, unfolding, and aggregation. Structural, studies have so far provided static snapshots on the behavior of the, wild-type enzyme and some of the FALS mutants. New approaches are required, to map out the structural trajectories of the molecule. Here, using our, 1.15-A resolution structure of fully metallated human SOD1 and highly, parallelized molecular dynamics code on a high-performance capability, computer, we have undertaken molecular dynamics calculations to 4,000 ps, to reveal the first stages of misfolding caused by metal deletion. Large, spatial and temporal fluctuations of the "electrostatic" and "Zn-binding", loops adjacent to the metal-binding sites are observed in the apo-enzyme, relative to the fully metallated dimer. These early misfolding events, expose the beta-barrels of the dimer to the external environment, allowing, close interactions with adjacent molecules. Protection of the beta-edge of, the protein can be partially restored by incorporating a single Zn, molecule per dimer. These calculations reveal an essential step in the, formation of the experimentally observed self-aggregations of, metal-depleted FALS mutant SOD1. This result also has implications for the, role of demetallated wild-type SOD1 in sporadic cases of ALS, for which, the molecular cause still remains undiscovered.

Disease

Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]

About this Structure

2V0A is a Single protein structure of sequence from Homo sapiens with CU, ZN, SO4 and ACT as ligands. Active as Superoxide dismutase, with EC number 1.15.1.1 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Molecular dynamics using atomic-resolution structure reveal structural fluctuations that may lead to polymerization of human Cu-Zn superoxide dismutase., Strange RW, Yong CW, Smith W, Hasnain SS, Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10040-4. Epub 2007 Jun 4. PMID:17548825

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