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2nnx
From Proteopedia
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| , resolution 2.30Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | SOD1 (Homo sapiens) | ||||||
| Activity: | Superoxide dismutase, with EC number 1.15.1.1 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of the H46R, H48Q double mutant of human [Cu-Zn] Superoxide Dismutase
Contents |
Overview
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.
Disease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this Structure
2NNX is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Mon Mar 31 04:05:44 2008
