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Principal Investigator: Philippe Youkharibache
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2024
Award: $42,813
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. A study by Dr. Marc Sitbon and collaborators identified 187 endoRBDs that exhibit predicted structures that can be grouped in a number of clusters. Recent analyses on primates endoRBDs show conservation demonstrating « positive and purifying selections » for most. A patent has been filed on endoRBD polypeptides capable of specifically recognizing and binding to the neutral amino acid transporter ASCT1/SLC1A4, while not binding to the related neutral amino acid transporter ASCT2/SLC1A5. The present invention further relates to in vitro and in vivo methods of specifically detecting or/and measuring the level of ASCT1, and to the use of said polypeptides in diagnosis and therapy (https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024121254and_gid=202424).
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Amino Acids><Animals><Anti-viral Agents><Antigenic Determinants><Arginine><Baboons><Binding><Binding Determinants><Biological Markers><Bovine Leukemia Virus><Bovine leukemia><CCL21><CCL21 gene><CKb9><COVID-19 virus><COVID19 virus><Cat Leukemia Virus><Cattle Leukemia Virus><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Surface Proteins><Cell Surface Receptors><Cell surface><Cells><Cellular Metabolic Process><CoV-2><CoV2><Collaborations><Complex><Computer software><Coronaviridae><Coronavirus><D-Glucose><Data><Development><Dextrose><Diagnosis><ERVs><Endogenous Retroviruses><Epitheliasin Gene><Epitopes><Erythrocyte/Hepatoma Glucose Transporter><Exhibits><Family><FeLV><Feline Leukemia Virus><Feline Lymphoma Virus><France><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GLUT><GLUT1><GPCR><GeneHomolog><Gln><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose Transporter 1><Glutamine><Glycoproteins><Goals><HERVs><HTLV Viruses><HTLV group><Homolog><Homologous Gene><Homologue><Human><Human Endogenous Retroviruses><Human Genome><Human T-Cell Leukemia Viruses><Human T-Cell Leukemia-Lymphoma Viruses><Human T-lymphotropic Viruses><Immune response><Immunological response><In Vitro><Inflammation><L-Arginine><L-Glutamine><L-Serine><Legal patent><Ligands><MGC34555><Measures><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methodology><Methods><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Neutral Amino Acid Transport Proteins><Neutral Amino Acid Transport Systems><Neutral Amino Acid Transporters><Normal Cell><Nutrient><Oncogenesis><Oncogenic><PRSS10><Papio><Papios><Paris><Paris, France><Patents><Play><Primates><Primates Mammals><Process><Proteins><Q Levoglutamide><Q. Levoglutamide><Receptor Cell><Receptor Protein><Research><Retroviridae><Retroviruses><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA21><SLC><SLC2A1><SLC2A1 gene><Savanna Baboons><Serine><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Software><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Specificity><Structure><Supersecondary Protein Structure><Surface Proteins><System><TCA4><TMPRSS2><TMPRSS2 gene><Viral Diseases><Viral Receptor><Virus Diseases><Virus Receptors><Virus-Retrovirus><Wuhan coronavirus><Zwitterionic Amino Acid Transport Proteins><Zwitterionic Amino Acid Transport Systems><Zwitterionic Amino Acid Transporters><aminoacid><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-cancer><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><beta CoV><beta coronavirus><betaCoV><betacoronavirus><bio-markers><biologic marker><biomarker><cell metabolism><cellular differentiation><cellular metabaolism><computational pipelines><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><data-driven model><design><designing><develop software><developing computer software><developmental><enverin><hCoV19><host response><human whole genome><immune system response><immunoresponse><improved><in vivo><innovate><innovation><innovative><invention><member><model building><nCoV2><polypeptide><receptor><receptor binding><receptor bound><social role><software development><syncytin><tool><tumorigenesis><viral infection><virus envelope><virus infection><virus-induced disease><β CoV><β coronavirus><βCoV>