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

Vijayakrishnan, S. , Callow, P., Nutley, M.A., McGow, D.P., Kropholler, P., Cooper, A., Byron, O. and Lindsay, J.G. (2011) Variation in the organization and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly. Biochemical Journal, 437(3), pp. 565-574. (doi:10.1042/BJ20101784)

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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 cor

Item Type:Articles
Additional Information:The final version of record is available at http://www.biochemj.org/bj/default.htm
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vijayakrishnan, Dr Swetha and Kropholler, Prof Peter and Lindsay, Professor Gordon and Nutley, Mrs Margaret and Cooper, Professor Alan and Byron, Professor Olwyn
Authors: Vijayakrishnan, S., Callow, P., Nutley, M.A., McGow, D.P., Kropholler, P., Cooper, A., Byron, O., and Lindsay, J.G.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Science and Engineering > School of Chemistry
College of Science and Engineering > School of Computing Science
College of Science and Engineering > School of Mathematics and Statistics > Mathematics
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Biochemical Journal
Publisher:Portland Press Ltd.
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:31 May 2011
Copyright Holders:Copyright © 2011 Biochemical Society
First Published:First published in Biochemical Journal 437(3):565-574
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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