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

R. Max Wynn, Masato Kato, Mischa MacHius, Jacinta L. Chuang, Jun Li, Diana R. Tomchick, David T. Chuang

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The human mitochondrial branched-chain α-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-α 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-α that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-α does not severely impede the E1b-dependent decarboxylation of α-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 α-ketoacid dehydrogenase complexes by phosphorylation.

Original languageEnglish (US)
Pages (from-to)2185-2196
Number of pages12
JournalStructure
Volume12
Issue number12
DOIs
StatePublished - Dec 2004

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Phosphorylation
Thiamine Pyrophosphate
Decarboxylation
Acylation
Phosphoric Monoester Hydrolases
Serine
Catalytic Domain
Oxidoreductases
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Molecular mechanism for regulation of the human mitochondrial branched-chain α-ketoacid dehydrogenase complex by phosphorylation. / Wynn, R. Max; Kato, Masato; MacHius, Mischa; Chuang, Jacinta L.; Li, Jun; Tomchick, Diana R.; Chuang, David T.

In: Structure, Vol. 12, No. 12, 12.2004, p. 2185-2196.

Research output: Contribution to journalArticle

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AU - Li, Jun

AU - Tomchick, Diana R.

AU - Chuang, David T.

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