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Principal Investigator: Philippe Youkharibache
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2020
Award: $28,601
Funding agency: National Cancer Institute
A significant part of my recent research efforts is focused on studying self-association determinants of molecular systems as revealed by their structural symmetries at several levels: from proteins assemblies to their protein supersecondary structures constituents (protodomains) [Youkharibache 2019]. We have shown in particular that many important structural families of Polytopic Helical Membrane Proteins followed a common Pseudo-Symmetric evolutionary process in their construction [Youkharibache, Tran, and Abrol 2020]. This is the case for G protein-coupled receptors (GPCRs), SLCs with an MFS fold such as SLC2A1/GLUT1, a glucose transporter used as a receptor by HTLV, or SLC7A1/CAT1, an arginine transporter and a receptor for mouse and bovine leukemia retroviruses. Our structural analyses have been enabled by innovative software that we developed in collaboration with NCBI [Wang et al. 2020], and a significant body of structural data has been obtained, that we are now harnessing to study their interactions with protein ligands on cell surfaces. Vertebrate retroviruses as different as the Human T-cell leukemia virus (HTLV) and the bovine leukemia virus, the large family of simian/murine/feline leukemia viruses, and many members of the non-infectious human endogenous retroviruses (HERV) that are constitutively present in the human genome, use their receptor-binding domains (RBDs) in the virus envelope glycoprotein to bind nutrient transporters of the SLC family as an initial step in cell entry. SLCs condition cell metabolism and their expression is systematically altered during normal cell differentiation and oncogenic processes. In collaboration with the IGMM (CNRS Montpellier, France) and the start-up Metafora-biosystems (Paris, France), we aim to study RBDs that bind SLCs that play a key role in oncogenic processes and immune response: notably the transporters of glucose and amino acids including glutamine, serine, and arginine. Among the family of RBDs that can commonly or distinctively bind glutamine and/or other neutral amino acid transporters (SLC1A5/ASCT2 and SLC1A4/ASCT1, respectively) are the BaEV and HERV-W RBDs. Another family of RBDs that distinctively bind glucose or arginine transporters - SLC2A1/GLUT1 and SLC7A1/CAT1 - includes the HTLV and BLV RBDs, respectively. We aim to study structural interactions between viral RBDs and SLCs and the role of SLCs in viral infections, oncogenesis, and immunological responses. Elucidating RBD-SLC interactions will also help designing synthetic SLC modulators either directly derived from RBDs or designed de novo. Recently, it was shown that SARS-CoV2 RBD binds to a receptor complex that includes ACE2, TMPRSS2, but also SLC6A19, a glutamine and other neutral amino acids transporters that also belongs to the SLC superfamily. We have performed initial structural analyses and developed structural analysis tools to enable collaborative research, especially on cell surface proteins-RBD interactions [Youkharibache et al. 2020]. The software and pipelines are being improved to support the aims of the project.
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