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Type: Journal article
Title: Variation in the organization and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly
Author: Vijayakrishnan, S.
Callow, P.
Nutley, M.
McGow, D.
Gilbert, D.
Kropholler, P.
Cooper, A.
Byron, O.
Lindsay, J.
Citation: Biochemical Journal, 2011; 437(3):565-574
Publisher: Biochemical Society
Issue Date: 2011
ISSN: 0264-6021
Statement of
Swetha Vijayakrishnan, Philip Callow, Margaret A. Nutley, Donna P. McGow, David Gilbert, Peter Kropholler, Alan Cooper, Olwyn Byron and J. Gordon Lindsay
Abstract: Crucial to glucose homoeostasis in humans, the hPDC (human pyruvate dehydrogenase complex) is a massive molecular machine comprising multiple copies of three distinct enzymes (E1–E3) and an accessory subunit, E3BP (E3-binding protein). Its icosahedral E2/E3BP 60-meric ‘core’ provides the central structural and mechanistic framework ensuring favourable E1 and E3 positioning and enzyme co-operativity. Current core models indicate either a 48E2+12E3BP or a 40E2+20E3BP subunit composition. In the present study, we demonstrate clear differences in subunit content and organization between the recombinant hPDC core (rhPDC; 40E2+20E3BP), generated under defined conditions where E3BP is produced in excess, and its native bovine (48E2+12E3BP) counterpart. The results of the present study 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 modelling 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 mammalian PDC comprises a heterogeneous population of assemblies incorporating a network of E3 (and possibly E1) cross-bridges above the core surface.
Keywords: E3-binding stoichiometry; E2/E3BP core organization; isothermal titration calorimetry (ITC); pyruvate dehydrogenase complex; small-angle neutron scattering (SANS); variable substitution model
Rights: Copyright The Authors Journal compilation Copyright 2011 Biochemical Society
RMID: 0030000969
DOI: 10.1042/bj20101784
Appears in Collections:IPAS publications
Environment Institute Leaders publications

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