Download The architecture of pyruvate dehydrogenase complexes determined

The architecture of pyruvate dehydrogenase complexes determined with
AUC, SAXS and SANS
O. Byron1, M. L. Laine2, J. G. Lindsay3, S. Müller2 and S. Vijayakrishnan4
1
School of Life Sciences, 2Institute of Infection, Immunity and Inflammation, 3Institute of Molecular, Cell and
Systems Biology, 4Centre for Virus Research
University of Glasgow, Glasgow G12 8QQ, United Kingdom
[email protected]
Crucial to glucose homoeostasis in humans, pyruvate dehydrogenase complex (PDC) 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. In this talk I will describe how we have
successfully used combined and complementary biochemical and biophysical techniques,
including small angle X-ray and neutron scattering (SAXS, SANS) and analytical
ultracentrifugation (AUC) to determine, for the first time, the architecture of the core human
complex 1; 2. Comparision of this with our recent data for PDC from the human malarial
parasite Plasmodium falciparum confirms our hypothesis that P. falciparum PDC is a
potential and novel anti-malarial drug target.
Solution structure of a truncated form of an ab initio
model generated from SANS data for human PDC
(red spheres) superimposed on a homology model of
truncated human PDC. Taken from Vijayakrishnan
et al. 2010.
References
1.
Vijayakrishnan, S., Kelly, S. M., Gilbert, R. J. C., Callow, P., Bhella, D., Forsyth, T., Lindsay, J. G. &
Byron, O. (2010). Solution structure and characterisation of the human pyruvate dehydrogenase complex
core assembly. Journal of Molecular Biology 399, 71-93.
2.
Vijayakrishnan, S., Callow, P., Nutley, M. A., McGow, D., Gilbert, D., Kropholler, P., Cooper, A., Byron,
O. & Lindsay, J. G. (2011). Variation in the organisation and subunit composition of the mammalian
pyruvate dehydrogenase complex E2/E3BP core assembly. Biochemical Journal 437, 565-574.