Septin filaments: structure, polymerization and role in pathologies

Abstract

Septins are cytoskeletal GTP-binding proteins involved in key cellular events including cytokinesis, vesicle trafficking and exocytosis. In humans, different septins self-associate in a specific manner to form hexameric or octameric heterocomplexes. These interact via their extremities to form filaments which are capable of assembling into higher order structures. It is known that ectopic expression, deletion and/or mutation of septin-coding genes is associated with a wide range of pathologies including infertility, neuropathies and several types of tumour. In the nervous system, for example, where septins are abundant and involved in almost all stages of neuronal development, abnormalities in the expression and function of septins has been associated with aging a neurodegenerative disorder. A complete understanding of the physiological roles of septins and the dysfunctions which lead to different pathologies with which they are associated, demands a wider knowledge of all aspects of the biochemical context where septins are important components. Amongst others, critical aspects include a better understanding of: their three-dimensional structure and its relationship with GTP binding and hydrolysis; the phenomenon of polymerization and membrane association; the organization of higher-order structures (bundles, networks etc.); their protein binding partners; the gene expression patterns of different tissues. With a view to clarifying several of these physiological aspects of septin function, the applicants (who are responsible for the greater part of our current knowledge concerning the structures of septins and their filaments) propose the use of e series of complementary approaches including the determination of further three-dimensional structures using X-ray diffraction and cryo-electron microscopy, the identification of septin binding partners in vivo using APEX technology and the analysis of gene expression profiles in the brain. Specific examples of the contributions we expect to make include understanding the mechanism associated with septin 2 cleavage by the NS3/2b protein from zika virus which is believed to be associated with neuropathy and the study of the association between septins and botulinum toxin light chains. (AU)