Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation

Fogel, Adam I.; Stagi, Massimiliano; Arce, Karen Perez de; Biederer, Thomas

doi:10.1038/emboj.2011.336

Cited by 64 publications

(82 citation statements)

References 44 publications

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“…Thus, this work suggests that weaker preformed cis-dimers of TIGIT on the cell surface are required for cis-trans receptor oligomerization that is necessary for PVR signaling into primary cells. A similar coupling of cis-trans dimerization has been investigated for the covalent cishomodimers in the CTLA-4-B7-1/2 complexes and for noncovalent cis-homodimers in cadherins as well as in the CAR-JAML complex and the Necl-SynCAM2 (12,13,25,(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

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.

165

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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Section: Discussionmentioning

confidence: 99%

“…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%

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.

165

159

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show abstract

“…In addition to the contribution of V-set domain in the dimer formation, previous cell biological studies indicated that the C-set domains of nectin or nectin-like molecules are involved in cis-interaction (Fig. 7A) (33)(34)(35). Related studies from different groups independently demonstrated that the C-set domains of nectin-2 and Necl-2 (SynCAM1) on the surface of the cells are responsible for the lateral clustering of the cis-interaction, which could complement or even promote the trans-interaction of these molecules (33,35).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies suggested that nectins/Necls might form cisdimers through their first C-set domain and consequently form trans-dimers through their V-set domain during cell-cell adhesion (28,(33)(34)(35). This interactive mode of nectins/Necls may be supported by the structural determination of the Necl-1 (also known as synaptic CAM [SynCAM]3) V-set domain in 2006, in which the homodimer of Necl-1 was considered a trans-dimer (36).…”

mentioning

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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“…We added bis-sulfosuccinimidyl suberate (BS 3 ), an 11-Å -long cross-linker, to cells co-transfected with SynCAM1-HA and SynCAM1-Flag, and SynCAM1-HA and SynCAM2-Flag. Co-transfection of SynCAM1-HA and SynCAM1-Flag served as a positive control because SynCAM1 is known to form homophilic cis-complexes (Fogel et al, 2011). To make sure that trans-interactions did not confound our results, we re-plated transfected cells at low density.…”

Section: Syncams Form Homophilic and Heterophilic Cis-and Transinteramentioning

confidence: 99%

The SynCAM synaptic cell adhesion molecules are involved in sensory axon pathfinding by regulating axon-axon contacts

Frei¹,

Andermatt²,

Gesemann³

et al. 2015

Development

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Synaptic cell adhesion molecules (SynCAMs) are crucial for synapse formation and plasticity. However, we have previously demonstrated that SynCAMs are also required during earlier stages of neural circuit formation because SynCAM1 and SynCAM2 (also known as CADM1 and CADM2, respectively) are important for the guidance of post-crossing commissural axons. In contrast to the exclusively homophilic cis-interactions reported by previous studies, our previous in vivo results suggested the existence of heterophilic cis-interactions between SynCAM1 and SynCAM2. Indeed, as we show here, the presence of homophilic and heterophilic cisinteractions modulates the interaction of SynCAMs with transbinding partners, as observed previously for other immunoglobulin superfamily cell adhesion molecules. These in vitro findings are in agreement with results from in vivo studies, which demonstrate a role for SynCAMs in the formation of sensory neural circuits in the chicken embryo. In the absence of SynCAMs, selective axon-axon interactions are perturbed resulting in aberrant pathfinding of sensory axons.

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Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation

Cited by 64 publications

References 44 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

The SynCAM synaptic cell adhesion molecules are involved in sensory axon pathfinding by regulating axon-axon contacts

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