2hrn
From Proteopedia
Solution Structure of Cu(I) P174L-HSco1
Structural highlights
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Disease[SCO1_HUMAN] Defects in SCO1 are a cause of mitochondrial complex IV deficiency (MT-C4D) [MIM:220110]; also known as cytochrome c oxidase deficiency. A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, excercise intolerance, developmental delay, delayed motor development and mental retardation. A subset of patients manifest Leigh syndrome.[1] [2] Function[SCO1_HUMAN] Thought to play a role in cellular copper homeostasis, mitochondrial redox signaling or insertion of copper into the active site of COX.[3] [4] [5] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe pathogenic mutant (P174L) of human Sco1 produces respiratory chain deficiency associated with cytochrome c oxidase (CcO) assembly defects. The solution structure of the mutant in its Cu(I) form shows that Leu-174 prevents the formation of a well packed hydrophobic region around the metal-binding site and causes a reduction of the affinity of copper(I) for the protein. K(D) values for Cu(I)WT-HSco1 and Cu(I)P174L-HSco1 are approximately 10(-17) and approximately 10(-13), respectively. The reduction potentials of the two apo proteins are similar, but slower reduction/oxidation rates are found for the mutant with respect to the WT. The mitochondrial metallochaperone in the partially oxidized Cu(1)(I)Cox17(2S-S) form, at variance with the fully reduced Cu(4)(I)Cox17, interacts transiently with both WT-HSco1 and the mutant, forming the Cox17/Cu(I)/HSco1 complex, but copper is efficiently transferred only in the case of WT protein. Cu(1)(I)Cox17(2S-S) indeed has an affinity for copper(I) (K(D) approximately 10(-15)) higher than that of the P174L-HSco1 mutant but lower than that of WT-HSco1. We propose that HSco1 mutation, altering the structure around the metal-binding site, affects both copper(I) binding and redox properties of the protein, thus impairing the efficiency of copper transfer to CcO. The pathogenic mutation therefore could (i) lessen the Sco1 affinity for copper(I) and hence copper supply for CcO or (ii) decrease the efficiency of reduction of CcO thiols involved in copper binding, or both effects could be produced by the mutation. Human Sco1 functional studies and pathological implications of the P174L mutant.,Banci L, Bertini I, Ciofi-Baffoni S, Leontari I, Martinelli M, Palumaa P, Sillard R, Wang S Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):15-20. Epub 2006 Dec 20. PMID:17182746[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Banci, L | Bertini, I | Ciofi-Baffoni, S | Leontari, I | Martinelli, M | Palumaa, P | SPINE, Structural Proteomics in Europe | Sillard, R | Wang, S | Chaperone | Disease mutation | Metal binding | Metal transport | Mitochondrion | Spine | Structural genomic | Structural proteomics in europe
