2nnx
Crystal Structure of the H46R, H48Q double mutant of human [Cu-Zn] Superoxide Dismutase
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OverviewOverview
A subset of superoxide dismutase 1 (Cu/Zn-SOD1) mutants that cause, familial amyotrophic lateral sclerosis (FALS) have heightened reactivity, with (-)ONOO and H(2)O(2) in vitro. This reactivity requires a copper ion, bound in the active site and is a suggested mechanism of motor neuron, injury. However, we have found that transgenic mice that express, SOD1-H46R/H48Q, which combines natural FALS mutations at ligands for, copper and which is inactive, develop motor neuron disease. Using a direct, radioactive copper incorporation assay in transfected cells and the, established tools of single crystal x-ray diffraction, we now demonstrate, that this variant does not stably bind copper. We find that single, mutations at copper ligands, including H46R, H48Q, and a quadruple mutant, H46R/H48Q/H63G/H120G, also diminish the binding of radioactive copper., Further, using native polyacrylamide gel electrophoresis and a yeast, two-hybrid assay, the binding of copper was found to be related to the, formation of the stable dimeric enzyme. Collectively, our data demonstrate, a relationship between copper and assembly of SOD1 into stable dimers and, also define disease-causing SOD1 mutants that are unlikely to robustly, produce toxic radicals via copper-mediated chemistry.
DiseaseDisease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this StructureAbout this Structure
2NNX is a Single protein structure of sequence from Homo sapiens with ZN, SO4 and ACE as ligands. Active as Superoxide dismutase, with EC number 1.15.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Disease-associated mutations at copper ligand histidine residues of superoxide dismutase 1 diminish the binding of copper and compromise dimer stability., Wang J, Caruano-Yzermans A, Rodriguez A, Scheurmann JP, Slunt HH, Cao X, Gitlin J, Hart PJ, Borchelt DR, J Biol Chem. 2007 Jan 5;282(1):345-52. Epub 2006 Nov 8. PMID:17092942
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