title: Evidence for carbohydrate recognition and homotypic and heterotypic binding by the TIM family.
abstract: The T cell Ig domain and mucin domain (TIM) proteins form a conserved family of transmembrane cell-surface glycoproteins expressed by a variety of tissues. Each TIM protein contains a single V-type Ig domain, a glycosylated mucin-like domain, a transmembrane domain and a cytoplasmic domain. TIM proteins recognize a diverse array of ligands, including H-ferritin, galectin-9 as well as other TIM family members. In this study, we demonstrate that the Ig domains of murine TIM-1, -3 and -4 display calcium-dependent binding to ligands expressed by murine splenocytes and several non-murine cell lines, indicating non-species-specific ligand recognition. Further, the intrafamilial interaction of various TIM family Ig domains with surface-expressed TIM-1 and TIM-4 requires an intact TIM-1 and TIM-4 glycosylated mucin stalk. Importantly, we also uncovered the previously unrecognized potential for homotypic TIM interactions in forming ligand-receptor pairs. Using a glycan array screen, we identified the novel capacity of the TIM-3 Ig domain to recognize specific carbohydrate moieties, suggesting a role for carbohydrate modification along with protein epitopes in TIM ligand recognition. Identification of the carbohydrate-binding capacity of TIM proteins helps explain the diversity of ligands recognized by this family and adds to our understanding of homotypic and heterotypic interactions between TIM family members.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Wilker
authors.forename: John R
authors.initials: JR
authors.lastname: Sedy
authors.forename: Vadim
authors.initials: V
authors.lastname: Grigura
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004533:Egtazic Acid / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D000072597:Hepatitis A Virus Cellular Receptor 2; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018411:Spodoptera; D014162:Transfection
chemical_list: D002118:Calcium; D002809:Chondroitin Sulfates; D004533:Egtazic Acid; D006497:Heparan Sulfate; D000072596:Hepatitis A Virus Cellular Receptor 1; D000072597:Hepatitis A Virus Cellular Receptor 2; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011134:Polysaccharides; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C442240:Havcr1 protein, mouse; C442241:Havcr2 protein, mouse; C500399:TIM-4 protein, mouse