Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2

Dibyendu Samanta, Haisu Guo, Rotem Rubinstein, Udupi A. Ramagopal, Steven C. Almo

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)151-159
Number of pages9
JournalMolecular Immunology
Volume81
DOIs
StatePublished - Jan 1 2017

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T-Cell Antigen Receptor
T-Lymphocytes
Natural Killer Cells
Immunoglobulins
nectins
Immunoglobulin Domains
Ligands
Antigens
Antigen-Presenting Cells
Autoimmunity
Cell Communication
Observation
Peptides

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

Cite this

Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2. / Samanta, Dibyendu; Guo, Haisu; Rubinstein, Rotem; Ramagopal, Udupi A.; Almo, Steven C.

In: Molecular Immunology, Vol. 81, 01.01.2017, p. 151-159.

Research output: Contribution to journalArticle

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