ACTIN-NUCLEATORS · Structural studies of actin nucleator complexes

Actin is one of the most conserved globular proteins among diverse species. It plays a major role in many important cellular processes that range from muscle contraction, cell motility, cell division and cytokinesis to vesicle/organelle-movement, cell signaling, maintenance of cell junctions and shape. Actin filaments are major determinants of cell morphology and are sites for focal adhesion in multicellular organisms. Actin filaments nucleate from free actin monomers to form oligomeric assemblies at specified subcellular compartments in response to different signaling cascades. Research in the field of actin-nucleator complexes (ANC) has been highly encouraged in the last few years due to finding of a growing number of actin nucleators that have been identified to play vital role in the architecture, regulation and function of the cell. Any alterations in actin polymerization or complex formation can lead to severe health concerns for the human beings. At present there are over 27 different ANC that have been identified, but understanding of their structural and functional processes is still a major challenge. Therefore, the aim of this research proposal is to understand the different actin nucleation mechanisms that also involve conformational differences, which occur when in complex with actin. To understand the precise structure-function aspects of ANC, we plan to determine the three-diamensional structure of different actin nucleators in native and in complex with actin, this involves full length forming homology domain (FHOD1) nucleator factor and WH2-containg nucleators. Guided by the final three-dimensional structural knowledge, it will be possible to explore the function of actin assembly in human physiology that will ultimately be used towards clinical applications.