Structure of Herpes Simplex Virus Glycoprotein D Bound to the Human Receptor Nectin-1

Giovine, Paolo Di; Settembre, Ethan C.; Bhargava, Arjun; Luftig, Micah A.; Lou, Huan; Cohen, Gary H.; Eisenberg, Roselyn J.; Krummenacher, Claude; Carfı́, Andrea

doi:10.1371/journal.ppat.1002277

Cited by 163 publications

(228 citation statements)

References 75 publications

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“…S3C). This overlap of ligand and virus binding sites also has been reported for other virus receptors (9,25).…”

Section: Resultssupporting

confidence: 79%

“…3 A and B), allowing for the formation of a TIGIT lateral cis-homodimer on cells. A similar crystal packing has also been described for Nectin-1 in complex with glycoprotein D from herpes simplex virus (9). The interface of this TIGIT homodimer buries a total molecular surface area of about 1,000 Å 2 and uses the flat surface of the four-stranded β-sheet on the back of the molecule (Fig.…”

Section: Resultsmentioning

confidence: 60%

“…Several high-affinity homophilic trans-interactions have been described in detail for nectins/Necls and similar molecules (8)(9)(10)(11)(12)(13). However, the structure and function of the presumably weaker lateral homophilic cis-dimers in cell adhesion and their role in intracellular signaling is not known.…”

mentioning

confidence: 99%

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Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Stengel¹,

Harden-Bowles²,

Yu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

159

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Nectins (nectin1-4) and Necls ] 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.N ectins (nectin1-4) and nectin-like (Necl1-5) molecules are members of the large Ig superfamily (IgSF) of cell-surface receptors that play central roles in cell adhesion, cell movement, proliferation, and survival and contribute to the morphogenesis and differentiation of many cell and tissue types by inducing an intracellular signaling cascade (1-5). Nectins and Necls can function as both ligands and receptors and therefore are able to signal bidirectionally into juxtaposed cells (3,6). To mediate the formation of cell adherens junctions, a model suggests that the extracellular domains of these molecules form ligand-dependent homo-or heterodimers in trans (between molecules located on the same or opposite cell surfaces, respectively) and lateral homodimers in cis, creating a tight network of nectin zippers between juxtaposed cells (7,8). To date, structural and functional studies suggest a mechanism whereby the cis-homodimerization of a receptor on the same cell surface is followed by the formation of a trans-dimer between juxtaposed cells using identical protein interfaces. This assembly is noteworthy because it requires a rearrangement and breakup of the cis-homodimer followed by a transdimerization across the adherens junction. The cis-trans clustering is then initiated through another unknown protein interface, likely involving a different receptor domain.Several high-affinity homophilic trans-interactions have been described in detail for nectins/Necls and similar molecules (8-13). However, the structure and function of the presumably weaker lateral homophilic cis-dimers in cell adhesion and their role in intracellular signaling is not known. Because all structures solved to date are homodimers, it is unclear if they represent the cisor the trans-state. Thus, the question of how cis-trans heterodimerization drives cell adhesion and intracellular sign...

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“…S3C). This overlap of ligand and virus binding sites also has been reported for other virus receptors (9,25).…”

Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 60%

See 1 more Smart Citation

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Stengel¹,

Harden-Bowles²,

Yu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

159

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“…Therefore, the true scenario of the structural basis for the diverse binding properties of nectins/Necls remains a big issue. Recently, our group (61) and Di Giovine et al (62) independently discovered that human HSV-1 glycoprotein D (gD) unexpectedly precluded the nectin-1 dimer from entering host cells (i.e., the binding interface of nectin-1 to gD is almost the same as the nectin-1 dimer interface), revealing the monomeric nectin-1 binding mode to gD, rather than the suspected nectin-1 dimeric binding.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226

Qian

Chen

et al. 2012

The Journal of Immunology

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The nectin and nectin-like molecule (Necl) family includes important cell adhesion molecules (CAMs) characterized by their Ig-like nature. Such CAMs regulate a broad spectrum of cell–cell interactions, including the interaction between NK cells and cytotoxic T lymphocytes (CTLs) and their target cells. CAM members nectin-2 (CD112) and Necl-5 (CD155) are believed to form homodimers (for nectin-2) or heterodimers in their functions for cell adhesion, as well as to interact with immune costimulatory receptor DNAX accessory molecule 1 (DNAM-1) (CD226) to regulate functions of both NK and CTL cells. However, the structural basis of the interactive mode of DNAM-1 with nectin-2 or Necl-5 is not yet understood. In this study, a soluble nectin-2 Ig-like V-set domain (nectin-2v) was successfully prepared and demonstrated to bind to both soluble ectodomain and cell surface-expressed full-length DNAM-1. The 1.85-Å crystal structure of nectin-2v displays a perpendicular homodimer arrangement, revealing the homodimer characteristics of the nectin and Necls. Further mutational analysis indicated that disruption of the homodimeric interface of nectin-2v led to a failure of the homodimer formation, as confirmed by crystal structure and biochemical properties of the mutant protein of nectin-2v. Interestingly, the monomer mutant also loses DNAM-1 binding, as evidenced by cell staining with tetramers and surface plasmon resonance assays. The data indicate that interaction with DNAM-1 requires either the homodimerization or engagement of the homodimeric interface of nectin-2v. These results have implications for immune intervention of tumors or autoimmune diseases in the DNAM-1/nectin-2–dependent pathway.

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“…Fırst, gD binds cell surface receptor and starts changes which allow for membrane fusion of other glycoproteins. Nectin-1 is a cell adhesion molecule, which gD binds and also the main HSV receptor found in epithelial cells and neurons [12,17,18].…”

Section: Structure Of Herpes Simplex Virusesmentioning

confidence: 99%

Genital Herpes

Emre¹,

Akkus²

2017

Fundamentals of Sexually Transmitted Infections

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Genital herpes simplex virus (HSV) infections are among the most commonly seen sexually transmited infections in the world. Genital herpes is a serious health problem because the infection continues through life with remissions and relapses, it causes recurring painful ulcers, and there is no known cure for it. The real prevalence of the genital herpes infection is unknown due to asymptomatic cases. The majority of infected individuals are not aware of the infection due to short duration of symptoms and signs or its asymptomatic nature. The clinical presentation of genital herpes shows certain differences in terms of the primary atack following the irst encounter with the virus and recurrent atacks. There is a strong relationship between HSV-2 positivity and human immunodeiciency virus (HIV). A serious complication of genital herpes in the mother during pregnancy, neonatal herpes, has a mortality risk of 60% if not treated. Antiviral therapy is safe and efective, for both episodic treatment and chronic suppression of HSV. Epidemiology, clinical presentation, laboratory, and treatment options of genital herpes are summarized in this chapter.

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Structure of Herpes Simplex Virus Glycoprotein D Bound to the Human Receptor Nectin-1

Cited by 163 publications

References 75 publications

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226

Genital Herpes

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