Ability of human WIP to functionally substitute for yeast Vrp1p/Verprolin in normal yeast cell growth

Wiskott Aldrich Syndrome is a genetic disease caused by a defect in the gene which is responsible for the production of WAS protein (WASp). Patients with WAS are associated with immunological disorders like thrombocytopenia, recurrent infections, eczema, low platelets count and compromised immunity. The main function of WASp is to regulate the actin cytoskeleton in hematopoietic cells, with crucial roles in lymphoid and myeloid cell migration, receptor signaling, phagocytosis and cytotoxicity. WASp promotes assembly of branched actin filaments and functions in a complex with WASP-interacting protein (WIP). WIP is 503 amino acid protein and has a significant and important role in proper functioning of WASp. Many components of the cytoskeleton are functionally and structurally conserved between human and yeast, which makes yeast an ideal organism to be used as a model. The yeast Saccharomyces cerevisiae has an actin cytoskeleton similar to mammalian cells and the homologues of WASP and WIP in S. Cerevisiae are Las17p and Vrp1p, respectively. In yeast, Vrp1p binds the SH3 (Src Homology 3) domain of Hof1p (homologue of fifteen 1 protein) through proline rich motifs (PRM), and this binding promotes cytokinesis while a lack of Vrp1p inhibits cytokinesis. The interactions between WIP and Hof1p are similar through protein rich motifs of WIP and SH3 domains of Hof1p. The interactions between WIP and Hof1p rescue the yeast from growth defects which is caused at high temperatures (37 ℃). Our hypothesis is, PRMs in WIP plays an important role in interacting with SH3 domains and rescuing yeast not only under the stress caused at high temperature, but also under oxidative and osmotic stress caused by H2O2 and NaCl, respectively. We also aim to find out if the deletion of PRMs can have some adverse effect on the growth and viability of yeast in presence of these stress conditions. [...]
Thesis (Masters)
Master of Medical Research (MMedRes)
School of Pharmacy & Med Sci
Griffith Health
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