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dc.contributor.authorVijayakrishnan, S-
dc.contributor.authorCallow, P-
dc.contributor.authorNutley, MA-
dc.contributor.authorMcGow, DP-
dc.contributor.authorGilbert, D-
dc.contributor.authorKropholler, P-
dc.contributor.authorCooper, A-
dc.contributor.authorByron, O-
dc.contributor.authorLindsay, JG-
dc.date.accessioned2012-06-01T10:39:31Z-
dc.date.available2012-06-01T10:39:31Z-
dc.date.issued2011-
dc.identifier.citationBiochemical Journal, 437: 565-574, 2011en_US
dc.identifier.issn0264-6021-
dc.identifier.urihttp://www.biochemj.org/bj/437/bj4370565.htmen
dc.identifier.urihttp://bura.brunel.ac.uk/handle/2438/6461-
dc.descriptionThe final version of this article is available at the link below.en_US
dc.description.abstractCrucial 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.en_US
dc.description.sponsorshipThis work was partly supported by EPSRC (under grants GR/R99393/01 and EP/C015452/1).en_US
dc.language.isoenen_US
dc.publisherBiochemical Societyen_US
dc.subjectE3-binding stoichiometryen_US
dc.subjectE2/E3BP core organizationen_US
dc.subjectIsothermal titration calorimetry (ITC)en_US
dc.subjectPyruvate dehydrogenase complexen_US
dc.subjectSmall-angle neutron scattering (SANS)en_US
dc.subjectVariable substitution modelen_US
dc.titleVariation in the organization and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assemblyen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1042/BJ20101784-
pubs.organisational-data/Brunel-
pubs.organisational-data/Brunel/Brunel (Active)-
pubs.organisational-data/Brunel/Brunel (Active)/School of Info. Systems, Comp & Maths-
pubs.organisational-data/Brunel/Research Centres (RG)-
pubs.organisational-data/Brunel/Research Centres (RG)/CIKM-
pubs.organisational-data/Brunel/School of Information Systems, Computing and Mathematics (RG)-
pubs.organisational-data/Brunel/School of Information Systems, Computing and Mathematics (RG)/CIKM-
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Computer Science
Dept of Computer Science Research Papers

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