Description du sujet de thèse

Phosphorylation by protein kinases (PK) is a major post-translational modification that influences almost all aspects of cell biology. PKs are expressed in eukaryotes, prokaryotes, and viruses. In eukaryotes, the most abundant branch of canonical PKs shares conserved sequence motifs and 3D structures in their catalytic domains, and phosphorylates Ser, Thr or Tyr residues in target proteins. In contrast, atypical PKs share little sequence identity or 3D structure and only represents about 10% of all eukaryotic PKs.
We made the serendipitous discovery that the giant virus, Pandoravirus dulcis, contained a putative PK, previously annotated as an ORFan. AlphaFold structure prediction and structural homolog searching showed that this protein contained classical “kinase motifs”, as well as additional domains with unknown function. Using this putative PK as a structural search model, we identified ~15 putative canonical and non-canonical PKs in each Pandoravirus strain. This project aims to elucidate the molecular details underlying these PKs activity, regulation, and interactions with partners by using a multidisciplinary approach using molecular biology, protein chemistry, structural biology and biophysics, enzymatic and innovative biosensor assay development. We expect that these integrated structural and functional studies of atypical kinases will allow identification of a novel PK signaling toolkit, including non-canonical PKs, non-canonical phosphorylation motifs, novel functions and regulatory mechanisms, to pave the way towards global understanding of PKs evolution in viruses and beyond.

Contexte de travail

The position is based in the “Structural Biology and Integrated Chemical Biology” (iSCB) team within the Centre for Cancer Research of Marseille (CRCM), located in Marseille. The CRCM laboratory is situated next to the Paoli-Calmettes Institute and near the Timone and Luminy campuses of Aix-Marseille University.
Research in the team is multidisciplinary and aims to identify, understand, and target protein-protein interactions in signaling pathways such as phosphorylation, using approaches in chemistry, biochemistry, biophysics, structural biology, high-throughput screening, and chemoinformatics (HiTS platform).