Webinar 8: November 11th, 12.00-13.00 (SAST); 11.00-12.00 (CET)

First talk:- Allosteric Inhibition in Aspartate Transcarbamylase:
Applications from malaria to herbicides

Speaker: Prof. Dr. Matthew Groves

Abstract: Pyrimidine biosynthesis is an essential function in all living cells and is supported by two distinct pathways: de novo synthesis and salvage. Different cell types are more dependent upon different pathways, but generally rapidly dividing cells are dependent on de novo synthesis. Aspartate transcarbamylase catalyses the first committed reaction in this pathway and is therefore an attractive drug target for multiple systems. However, the current ATCase gold standard inhibitor is a transition state mimic and has limited selectivity between human and pathogens. In this talk, I will describe the discovery of a new allosteric inhibitor of ATCase and its potential in multiple disease systems and as a herbicide.

Second talk:- The role of HOP in cytoskeletal organisation

Speaker: Dr. Kelly Schwarz

Abstract: Protein homeostasis is fundamental for cellular health. An essential molecular chaperone required for proteostasis is Hsp90, which aids the functional maturation of several hundred “client” proteins via their progression through the Hsp90 chaperone cycle. The Hsp70/Hsp90 Organising Protein (HOP) is a core co-chaperone of the Hsp90 chaperone cycle, and interacts with both Hsp70 and Hsp90 to mediate transfer of client proteins between the two chaperones. Overexpression of Hsp90 and HOP has been associated with malignancy, and many Hsp90 client proteins – which perform key roles in essential and diverse cellular processes – have been identified as oncoproteins that are overexpressed in cancer. HOP performs additional functions that are independent of its traditional co-chaperone role. HOP is found both intracellularly and extracellularly and in the extracellular milieu HOP appears to act as a cytokine, mediating multiple cellular processes in a prion protein (PrPC)-dependent and -independent manner, and independently of Hsp90. This represents an expanding repertoire of cellular roles described for HOP, contributing to our understanding of its biological impact in health and disease. In this talk I will consider some of the diverse functions of HOP with a focus on its role in cytoskeletal remodelling and cell migration, an essential cellular process that is exploited in tumorigenesis.

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