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Radio Conference "Chemistry for health"

Proposal for a Master 2 internship

Impact of the interaction of co-chaperone HSP40/DNAJ on the folding and stability of the von Hippel-Lindau tumour suppressor

Supervisors: Xavier LE GOFF et Olivier Delalande
Contact: (02 23 23 45 27)
Team: Molecular Bases of Tumorigenesis : VHL disease (Y. Arlot)
Bâtiment 4 pièce 306 - Faculté de Médecine Campus Santé
Institut de Génétique et Développement de Rennes (IGDR)- 35000 Rennes

To function properly in the cell, a polypeptide chain must adopt a conformation called a "native" state. In the absence of this structure or its maintenance in the cell, it is considered as "misfolded" which is most often accompanied by a loss of function. The HSP40 protein is a co-chaperone of HSP70; the HSP40/HSP70 complex controls the folding of proteins into a native, functional state. The von Hippel-Lindau tumor suppressor gene (VHL) was the first identified gene involved in the development of renal cell carcinoma (Renal Cell Carcinoma, RCC).  Inactivation of the VHL gene is an early and necessary step in the occurrence of 80% of sporadic CCRs of the most common subtype. In addition, germline mutations in this gene are responsible for the genetic syndrome of VHL, which predisposes patients to the formation of hypervascularized tumours throughout their lives. The VHL gene product (pVHL) is involved in multiple biological processes such as cell growth and differentiation and physiological response to hypoxia. pVHL proteins, like other proteins, can easily lose their native conformation when mutated. We are interested in mutations of pVHL found in CCR or VHL disease that are likely to affect its conformation and/or stability. We recently identified some HSP40 isoforms during a proteomic screen to look for pVHL protein partners.The aim of the internship is to understand the role of the interaction of HSP40 and pVHL protein through in silico, in vitro and in cellulo approaches.  To do this, we will characterize the interaction sequence between HSP40 and pVHL using recombinant proteins. The work will be supported by a theoretical approach in structural biology (molecular modelling). We will then study the role of this interaction in cellulo in an expression system developed in the fission yeast by the team. Finally, we will look for pVHL RCC mutations that impact this interaction.

Keywords: Protein folding / cancer / HSP40-HSP70 / VHL

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