Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex

Masato Kato, Jacinta L. Chuang, Shih Chia Tso, R. Max Wynn, David T. Chuang

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The human pyruvate dehydrogenase complex (PDC) is regulated by reversible phosphorylation by four isoforms of pyruvate dehydrogenase kinase (PDK). PDKs phosphorylate serine residues in the dehydrogenase (E1p) component of PDC, but their amino-acid sequences are unrelated to eukaryotic Ser/Thr/Tyr protein kinases. PDK3 binds to the inner lipoyl domains (L2) from the 60-meric transacetylase (E2p) core of PDC, with concomitant stimulated kinase activity. Here, we present crystal structures of the PDK3-L2 complex with and without bound ADP or ATP. These structures disclose that the C-terminal tail from one subunit of PDK3 dimer constitutes an integral part of the lipoyl-binding pocket in the N-terminal domain of the opposing subunit. The two swapped C-terminal tails promote conformational changes in active-site clefts of both PDK3 subunits, resulting in largely disordered ATP lids in the ADP-bound form. Our structural and biochemical data suggest that L2 binding stimulates PDK3 activity by disrupting the ATP lid, which otherwise traps ADP, to remove product inhibition exerted by this nucleotide. We hypothesize that this allosteric mechanism accounts, in part, for E2p-augmented PDK3 activity.

Original languageEnglish (US)
Pages (from-to)1763-1774
Number of pages12
JournalEMBO Journal
Volume24
Issue number10
DOIs
StatePublished - May 18 2005

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Pyruvate Dehydrogenase Complex
Adenosine Diphosphate
Adenosine Triphosphate
Crystal structure
Tail
Phosphorylation
Dimers
Protein Kinases
Serine
Amino Acid Sequence
Catalytic Domain
Oxidoreductases
Protein Isoforms
Phosphotransferases
Nucleotides
Amino Acids
pyruvate dehydrogenase (acetyl-transferring) kinase

Keywords

  • Bound lipoyl domain
  • Lipoyl-lysine binding pocket
  • Phosphorylation
  • Pyruvate dehydrogenase kinase 3
  • Type 2 diabetes

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. / Kato, Masato; Chuang, Jacinta L.; Tso, Shih Chia; Wynn, R. Max; Chuang, David T.

In: EMBO Journal, Vol. 24, No. 10, 18.05.2005, p. 1763-1774.

Research output: Contribution to journalArticle

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