title: Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2.
abstract: In addition to antigen-specific stimulation of T cell receptor (TCR) by a peptide-MHC complex, the functional outcome of TCR engagement is regulated by antigen-independent costimulatory signals. Costimulatory signals are provided by an array of interactions involving activating and inhibitory receptors expressed on T cells and their cognate ligands on antigen presenting cells. T cell immunoglobulin and ITIM domain (TIGIT), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or poliovirus receptor (PVR), inhibits activation of T and NK cells. Here we report the crystal structure of the human TIGIT ectodomain, which exhibits the classic two-layer β-sandwich topology observed in other immunoglobulin super family (IgSF) members. Biophysical studies indicate that TIGIT is monomeric in solution but can form a dimer at high concentrations, consistent with the observation of a canonical immunoglobulin-like dimer interface in the crystalline state. Based on existing structural data, we present a model of the TIGIT:nectin-2 complex and utilized complementary biochemical studies to map the nectin-binding interface on TIGIT. Our data provide important structural and biochemical determinants responsible for the recognition of nectin-2 by TIGIT. Defining the TIGIT:nectin-2 binding interface provides the basis for rational manipulation of this molecular interaction for the development of immunotherapeutic reagents in autoimmunity and cancer.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, New York, USA.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, USA.
authors.forename: Haisu
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, New York, USA.
authors.forename: Rotem
authors.initials: R
authors.lastname: Rubinstein
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, New York, USA; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Bangalore, India. Electronic address: ramagopal.udupi@gmail.com.
authors.forename: Udupi A
authors.initials: UA
authors.lastname: Ramagopal
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, New York, USA. Electronic address: steve.almo@einstein.yu.edu.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
mesh_terms: D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D000075983:Nectins; D011485:Protein Binding; D011487:Protein Conformation; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D015815:Cell Adhesion Molecules; D000075983:Nectins; D011971:Receptors, Immunologic; C534712:TIGIT protein, human