Small GTPases: a driving force behind formation of membrane microdomains



Andrew B. Goryachev, Centre for Systems Biology, University of Edinburgh

Tuesday February 24 , Location: MRC-LMCB, Time: 16.30



Many cells polarize for motility, directed growth or extension of processes. To initiate such polarized processes, cells first assemble sites of nascent protrusion as exquisitely focused membrane (micro)domains with high density of proteins that control actin polymerization and membrane delivery. Formation of these “hot spots” vitally requires activity of small Rho GTPases but their exact function in protein cluster assembly is still poorly understood. Our earlier modeling work (PLoS Comp. Biol. 2, 1511, 2006) suggested that active recruitment of GEFs and GAPs is involved but its mechanism remained obscure. Here, on the example of the early phase of yeast bud formation we provide a detailed mathematical analysis of the biochemical mechanism responsible for the assembly of the cluster of activated Cdc42 that defines the presumptive bud site. Employing detailed biophysical modeling, we show that Cdc42 nucleotide cycling coupled to its membrane-cytoplasmic shuttling is directly responsible for the self-organized assembly of the Cdc42 cluster (FEBS Lett. 582, 1437, 2008). We demonstrate that Cdc42 transforms cellular energy into a diffusive membrane-cytoplasmic flux which provides active recruitment of cluster components and prevents inevitable diffusive spreading of the cluster on the membrane. We identified a critical molecular element, a GTPase effector that binds and activates (stabilizes active conformation of) a GEF for the same GTPase, as required for this mechanism. We hypothesize that the mechanism we describe is widely used by cells in various intracellular contexts, especially those involving membrane trafficking.

Andrew's Webpage: http://www.biology.ed.ac.uk/research/institutes/cell/homepage.php?id=agoryachev

The talk will be followed by drinks in the Print room cafe. If you wish to meet with Andrew in the afternoon / evening, please contact Dorothy Bell (uccoadm@ucl.ac.uk).

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