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Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.

Wynn RM, Kato M, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT
Structure 12 2185-96 (2004)
Related entries: 1u5b, 1x7w, 1x7x, 1x7y, 1x7z

Cited: 36 times
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Abstract

The human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a 4 MDa macromolecular machine comprising three catalytic components (E1b, E2b, and E3), a kinase, and a phosphatase. The BCKDC overall activity is tightly regulated by phosphorylation in response to hormonal and dietary stimuli. We report that phosphorylation of Ser292-alpha in the E1b active site channel results in an order-to-disorder transition of the conserved phosphorylation loop carrying the phosphoryl serine. The conformational change is triggered by steric clashes of the phosphoryl group with invariant His291-alpha that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-alpha does not severely impede the E1b-dependent decarboxylation of alpha-ketoacids. However, the disordered loop conformation prevents phosphorylated E1b from binding the E2b lipoyl-bearing domain, which effectively shuts off the E1b-catalyzed reductive acylation reaction and therefore completely inactivates BCKDC. This mechanism provides a paradigm for regulation of mitochondrial alpha-ketoacid dehydrogenase complexes by phosphorylation.

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Related citations provided by authors (2)

  1. Crosstalk between Thiamin Diphosphate Binding and Phosphorylation Loop Conformation in Human Branched-Chain A-Ketoacid Decarboxylase/Dehydrogenase. Li J, Wynn RM, Machius M, Chuang JL, Karthikeyan S, Tomchick DR, Chuang DT J. Biol. Chem. 279 32968-32978 (2004)
  2. Roles of His291-Alpha and His146-Beta in the Reductive Acylation Reaction Catalyzed by Human Branched-Chain Alpha-Ketoacid Dehydrogenase: Refined Phosphorylation Loop Structure in the Active Site. Wynn RM, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT J. Biol. Chem. 278 43402-43410 (2003)

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