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- W3017118781 abstract "The mitochondrial cytochrome P450 24A1 (CYP24A1) is involved in deactivation of bioactive 1,25-(OH)2-vitD by side chain hydroxylation. Mutated CYP24A1 leads to idiopathic infantile hypercalcemia, characterized by elevated calcium, failure to thrive, vomiting, dehydration, and nephrocalcinosis. Deactivation relies on the protein-protein interaction with the redox partner, Adrenodoxin (Adx), housing the iron-sulfur cluster which provides two electrons for the hydroxylation step through reduction of heme iron in CYP24A1. We have previously used solution nuclear magnetic resonance (NMR) to demonstrate the long-range allostery of CYP24A1 in response to redox partner recognition. Here we report a comprehensive multidisciplinary approach using chemical cross-linking coupled to mass spectrometry, site-directed mutagenesis, NMR, functional assays and molecular dynamics simulations. Chemical crosslinking using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) traps a 1:1 CYP24A1-Adx complex by way of reaction with the carboxylate side chains of Adx and the primary amines of CYP24A1. Through chymotrypsin digest and mass spectrometry analysis of this product, we’ve identified a set of CYP24A1 peptides that are differentially modified, consistent with rearrangement of salt bridges in the presence or absence of substrate and Adrenodoxin. Affected sites include regions of the F-G helices, the A-helix, and the C/D elbow of the proximal surface. Interestingly, substrate-induced differential cross-linking at these sites only occurs when Adx is already present, suggesting a coordinated effect on CYP24A1 structure. This approach is combined with data from additional biophysical methods in order to inform a model of the functional 1:1 P450-Adx complex that is required for metabolism of vitamin-D." @default.
- W3017118781 created "2020-04-24" @default.
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- W3017118781 date "2020-04-01" @default.
- W3017118781 modified "2023-09-27" @default.
- W3017118781 title "Substrate 1,25(OH) 2 D3 and Adrenodoxin exert a coordinated change in CYP24A1 structure" @default.
- W3017118781 doi "https://doi.org/10.1096/fasebj.2020.34.s1.05623" @default.
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