title: Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering.
abstract: Nectins (nectin1-4) and Necls [nectin-like (Necl1-5)] are Ig superfamily cell adhesion molecules that regulate cell differentiation and tissue morphogenesis. Adherens junction formation and subsequent cell-cell signaling is initiated by the assembly of higher-order receptor clusters of cognate molecules on juxtaposed cells. However, the structural and mechanistic details of signaling cluster formation remain unclear. Here, we report the crystal structure of poliovirus receptor (PVR)/Nectin-like-5/CD155) in complex with its cognate immunoreceptor ligand T-cell-Ig-and-ITIM-domain (TIGIT). The TIGIT/PVR interface reveals a conserved specific "lock-and-key" interaction. Notably, two TIGIT/PVR dimers assemble into a heterotetramer with a core TIGIT/TIGIT cis-homodimer, each TIGIT molecule binding one PVR molecule. Structure-guided mutations that disrupt the TIGIT/TIGIT interface limit both TIGIT/PVR-mediated cell adhesion and TIGIT-induced PVR phosphorylation in primary dendritic cells. Our data suggest a cis-trans receptor clustering mechanism for cell adhesion and signaling by the TIGIT/PVR complex and provide structural insights into how the PVR family of immunoregulators function.
authors.affiliation: Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Stengel
authors.forename: Kristin
authors.initials: K
authors.lastname: Harden-Bowles
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Jianping
authors.initials: J
authors.lastname: Yin
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Comps-Agrar
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Dan L
authors.initials: DL
authors.lastname: Eaton
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
mesh_terms: D002448:Cell Adhesion; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor