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Article Dans Une Revue Biochemical Journal Année : 2011

Variation in the organisation and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly

Swetha Vijayakrishnan
  • Fonction : Auteur
Philip Callow
  • Fonction : Auteur
Margaret A Nutley
  • Fonction : Auteur
Donna P Mcgow
  • Fonction : Auteur
Gilbert David
Peter Kropholler
  • Fonction : Auteur
Alan Cooper
  • Fonction : Auteur
Olwyn Byron
  • Fonction : Auteur

Résumé

Crucial to glucose homeostasis in man, the human pyruvate dehydrogenase complex (hPDC) is a massive molecular machine comprising multiple copies of three distinct enzymes (E1-E3) and an accessory subunit, E3 binding protein (E3BP). Its icosahedral E2/E3BP 60-meric 'core' provides the central structural and mechanistic framework ensuring favourable E1 and E3 positioning and enzyme cooperativity. Current core models indicate either a 48E2+12E3BP or 40E2+20E3BP subunit composition. Here, we demonstrate clear differences in subunit content and organisation between recombinant hPDC core (rhPDC; 40E2+20E3BP), generated under defined conditions where E3BP is produced in excess, and its native bovine (48E2+12E3BP) counterpart. Our data provide a rational basis for resolving apparent differences between previous models, both obtained using rhE2/E3BP core assemblies where no account was taken of relative E2 and E3BP expression levels. Mathematical modeling predicts that an 'average' 48E2+12E3BP core arrangement allows maximum flexibility in assembly while providing the appropriate balance of bound E1 and E3 enzymes for optimal catalytic efficiency and regulatory fine-tuning. We also show that the rhE2/E3BP and bovine E2/E3BP cores bind E3s with a 2:1 stoichiometry and propose that hPDC comprises a heterogeneous population of assemblies incorporating a network of E3 (and possibly E1) cross-bridges above the core surface.

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Dates et versions

hal-00608398 , version 1 (13-07-2011)

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Swetha Vijayakrishnan, Philip Callow, Margaret A Nutley, Donna P Mcgow, Gilbert David, et al.. Variation in the organisation and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly. Biochemical Journal, 2011, 437 (3), pp.565-574. ⟨10.1042/BJ20101784⟩. ⟨hal-00608398⟩

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