1pu0 | pdb_00001pu0
Structure of Human Cu,Zn Superoxide Dismutase
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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 CU1, ZN and SO4 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 Mon Nov 12 18:47:15 2007
