1pu0

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spinqualitylabelsall models 1pu0, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structure of Human Cu,Zn Superoxide Dismutase

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

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

About this Structure

1PU0 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Superoxide dismutase, with EC number 1.15.1.1 Full crystallographic information is available from OCA.

Reference

ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization., DiDonato M, Craig L, Huff ME, Thayer MM, Cardoso RM, Kassmann CJ, Lo TP, Bruns CK, Powers ET, Kelly JW, Getzoff ED, Tainer JA, J Mol Biol. 2003 Sep 19;332(3):601-15. PMID:12963370

Page seeded by OCA on Thu Feb 21 14:32:31 2008