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Seminar by Professor Mohan Balasubramanian and Professor Robert Cross, Division of Biomedical Sciences, Warwick Medical School
'Allostery in microtubules' by Professor Robert Cross, Professor of Mechanochemical Cell Biology
Allostery, in which the binding of an effector switches a protein from one global conformation to another, was discovered and much-studied in the classical era of molecular biology. Influential models that accounted quantitatively for the switching behaviour were constructed.
More recently, it has been realised that allostery can happen even in natively unfolded proteins. This has lead to a new and wider view of allostery in which effectors serve to bias conformational dynamics, rather than flipping a conformational switch. It has also been realised that allosteric transitions occur in large ensembles of linked protein subunits. We and others are interested in allostery in microtubules, polymers of typically thousands of subunits in which dynamics and conformation and even geometry can all vary according to which effectors bind, and conversely, effector proteins can sense and respond to the local structure and conformation of the microtubule lattice. To really understand how microtubules work in complex in vivo contexts, we need to understand the range and power of these allosteric effects. Recent work in the group has used cryoEM (collab. with Carolyn Moores lab) to look at near-atomic resolution at the conformation of S. pombe MTs in complex with Mal3, in relation to the effects of Mal3 on dynamic instability.
Dan Peet has built a microfluidics framework for Nick Carter’s WOSM, and used it to look by TIRF-STORM at the effects of kinesin on the lattice spacing and dynamics of MTs. Algirdas Toleikis is looking at the effect of different MT lattices on the propensity of kinesin-1 to take backsteps. Naomi Sheppard is expressing and purifying mutant tubulins, aiming ultimately to understand the sequence determinants for allosteric drugs.