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3o55
From Proteopedia
Crystal structure of human FAD-linked augmenter of liver regeneration (ALR)
Structural highlights
DiseaseALR_HUMAN Congenital cataract - progressive muscular hypotonia - hearing loss - developmental delay. The disease is caused by mutations affecting the gene represented in this entry. FunctionALR_HUMAN Isoform 1: FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen.[1] [2] [3] [4] [5] Isoform 2: May act as an autocrine hepatotrophic growth factor promoting liver regeneration.[6] [7] [8] [9] [10] Publication Abstract from PubMedOxidative protein folding in the mitochondrial intermembrane space requires the transfer of a disulfide bond from MIA40 to the substrate. During this process MIA40 is reduced and regenerated to a functional state through the interaction with the flavin-dependent sulfhydryl oxidase ALR. Here we present the mechanistic basis of ALR-MIA40 interaction at atomic resolution by biochemical and structural analyses of the mitochondrial ALR isoform and its covalent mixed disulfide intermediate with MIA40. This ALR isoform contains a folded FAD-binding domain at the C-terminus and an unstructured, flexible N-terminal domain, weakly and transiently interacting one with the other. A specific region of the N-terminal domain guides the interaction with the MIA40 substrate binding cleft (mimicking the interaction of the substrate itself), without being involved in the import of ALR. The hydrophobicity-driven binding of this region ensures precise protein-protein recognition needed for an efficient electron transfer process. Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR.,Banci L, Bertini I, Calderone V, Cefaro C, Ciofi-Baffoni S, Gallo A, Kallergi E, Lionaki E, Pozidis C, Tokatlidis K Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4811-6. Epub 2011 Mar 7. PMID:21383138[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Banci L | Bertini I | Calderone V | Cefaro C | Ciofi-Baffoni S | Gallo A | Kallergi E | Lionaki E | Pozidis C | Tokatlidis K
