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Title: | Variation in the organization and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly |
Authors: | Vijayakrishnan, S Callow, P Nutley, MA McGow, DP Gilbert, D Kropholler, P Cooper, A Byron, O Lindsay, JG |
Keywords: | E3-binding stoichiometry;E2/E3BP core organization;Isothermal titration calorimetry (ITC);Pyruvate dehydrogenase complex;Small-angle neutron scattering (SANS);Variable substitution model |
Issue Date: | 2011 |
Publisher: | Biochemical Society |
Citation: | Biochemical Journal, 437: 565-574, 2011 |
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. |
Description: | The final version of this article is available at the link below. |
URI: | http://www.biochemj.org/bj/437/bj4370565.htm http://bura.brunel.ac.uk/handle/2438/6461 |
DOI: | http://dx.doi.org/10.1042/BJ20101784 |
ISSN: | 0264-6021 |
Appears in Collections: | Publications Computer Science Dept of Computer Science Research Papers |
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VijayakrishnanFINAL.pdf | 860.76 kB | Adobe PDF | View/Open |
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