Chemical reactions on cell surface modulated by active cytoskeleton

Abstract

This is a synopsis of the thesis entitled "Chemical Reactions on cell surface modulated by active cytoskeleton'. delivered by Bhaswati Bhattacharyya of the Theoretical Sciences Unit. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India. The thesis is divided into the following three parts. • Cell surface proteins such as lipid-tethcrcd GPl-anchorcd proteins and Ras-protcins are distributed as monomers and nanoclusters on the surface of living cells. Recent work from our laboratory suggested that the spatial distribution and dynamics of formation and breakup of these nanoclusters is controlled by the active remodelling dynamics of the underlying cortical actin. To t^xplain tlujse observations, a novel mechanism of active actin based clustering was proposed. Here we study the conse(iuences of such active actin-based clustering, in the context of chemical reactions involving conformational changes of cell surface proteins. W^ find that active remodelling of cortical actin, can give rise to a dramatic increase in the reaction efficiency and output levels. Our projjosai has implications for the kinetics of chemical reactions mediated by the constituents of such nanoclusters. in particular the cooperative ligand binding of ceil surface signalling receptors or enzymatic conversion as in a signalling complex. In general, such actin driven clustering of membrane proteins could be a cellular mechanism to spatiotcmporally regulate and amplify local chemical reaction rates, in the context of signalling and cndocytosis. In addition, we propose that the dynamics of protein conformational state changes via allostory can be used as a probe for the steady state dynamics of remodeling of cortical actin. We study the consequences of active actin-based clustering, in the context of conformational state changes of cell surface proteins using a M(?an Field approach, where the particles can b(! in the form of monomers or nanoclustcrs of size n. We find that active cortical actin remodeling can give rise to complete conformational spreading. Wc exhibit a phase diagram of 'spread of conformation' in the allostcryactivity plane, where the rate of tlu^ reactions are modulated by cortical actin. We explore these ideas in the special context of Ras-signailing on the cell surface. Ras-signalling ha.s l>een a widely studied mechanism [8]. Recent studies .show that these inner leaflet membrane receptors also maintain an organization of nanoclustcrs and monomers. Ras molecules signal when it is activated, i.e. GTP bound. This activation is mediated by an effector molecule SOS. SOS mok^eules have enhanccxl activity when it is localised to membrane. Wo study a sulvnetwork of the Ras-signalling cascade, and find that, the signalling efficiency and output can bu cnlianccd by the remodelling dynaniicy of actiu, which drives cell surface molculcs transiently bound to it.