期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2007
卷号：104
期号：1
页码：15-20
DOI：10.1073/pnas.0606189103
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The 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. KD values for Cu(I)WT-HSco1 and Cu(I)P174L-HSco1 are {approx}10-17 and {approx}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 Cu1(I)Cox172S-S form, at variance with the fully reduced Cu4(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. Cu1(I)Cox172S-S indeed has an affinity for copper(I) (KD {approx} 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.
关键词：cytochrome c oxidase ; mass spectrometry ; NMR ; copper chaperone ; respiratory chain deficiency
