Functional Cis-Heterodimers of N- and R-Cadherins

Shan, Weisong; Tanaka, Hidekazu; Phillips, Greg R.; Arndt, Kirsten; Yoshida, Mika; Colman, David; Shapiro, Lawrence

doi:10.1083/jcb.148.3.579

Cited by 182 publications

(184 citation statements)

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“…We presume that the complexes formed in intracellular compartments are precursors to SALM complexes on the cell surface and that cis interactions between the SALMs are present at the cell surface. (14,49). The specificity of these interactions is also dependent largely on the extracellular domains of cadherins (49).…”

Section: Discussionmentioning

confidence: 99%

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The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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Section: Discussionmentioning

confidence: 99%

“…(14,49). The specificity of these interactions is also dependent largely on the extracellular domains of cadherins (49).…”

Section: Discussionmentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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“…The W2-independent mechanism required the absence of Ca ++ . Additionally, Shan et al (2000) found R-cadherin/ N-cadherin heterocomplexes could be coimmunoprecipitated from cells expressing both cadherin subtypes. They showed also that the R-cadherin/N-cadherin interaction appears to be real because E-cadherin, if coexpressed with R-cadherin, is not coimmunoprecipitated with R-cadherin.…”

Section: Cadherin Adhesion Structure: Cis-dimermentioning

confidence: 96%

“…Cis-dimer formation has been further investigated by immunoprecipitation experiments without first crosslinking the proteins (Chitaev and Troyanovsky 1998;Klingelhofer et al 2000;Shan et al 2000). Immunoprecipitations showed complexes of cadherins believed to represent cis-dimers isolated from cell lysates.…”

Section: Cadherin Adhesion Structure: Cis-dimermentioning

confidence: 99%

Cadherin Adhesion: Mechanisms and Molecular Interactions

Perez

Nelson

2004

Handbook of Experimental Pharmacology

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Cadherins constitute a superfamily of cell-cell adhesion molecules expressed in many different cell types that are required for proper cellular function and maintenance of tissue architecture. Classical cadherins are the best understood class of cadherins. They are single membrane spanning proteins with a divergent extracellular domain of five repeats and a conserved cytoplasmic domain. Binding between cadherin extracellular domains is weak, but strong cell-cell adhesion develops during lateral clustering of cadherins by proteins that link the cadherin cytoplasmic domain to the actin cytoskeleton. Understanding how different regions of cadherins regulate cellcell adhesion has been a major focus of study. Here, we examine evidence of the structure and function of the extracellular domain of classical cadherins in regard to the control of recognition and adhesive contacts between cadherins on opposing cell surfaces. Early experiments that focused on understanding the homotypic, Ca ++ -dependent characteristics of cadherin adhesion are discussed, and data supporting the widely accepted cis-and trans-dimer models of cadherins are analyzed.

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“…To gain insight into the structural basis for DN-cadherin adhesive functions, we sought to obtain structures of DN-cadherin ectodomain regions. We initially focused on ectodomain fragments containing the four predicted N-terminal EC domains in the mature protein, partly because prior structural and functional studies on vertebrate classical-and T-cadherins showed that cell adhesion is mediated through the N-terminal EC domains (8,9,(21)(22)(23). We determined crystal structures of two DN-cadherin ectodomain fragments: one comprising domains EC1'-EC3' in two crystal forms (I and II), both to 2.5 Å resolution, and the other comprising domains EC1'-EC4' to 2.7 Å resolution.…”

mentioning

confidence: 99%

Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca ²⁺ -free interdomain linkers

Jin

Walker

Felsövályi

et al. 2011

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

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Vertebrate classical cadherins mediate selective calcium-dependent cell adhesion by mechanisms now understood at the atomic level. However, structures and adhesion mechanisms of cadherins from invertebrates, which are highly divergent yet function in similar roles, remain unknown. Here we present crystal structures of three-and four-tandem extracellular cadherin (EC) domain segments from Drosophila N-cadherin (DN-cadherin), each including the predicted N-terminal EC1 domain (denoted EC1') of the mature protein. While the linker regions for the EC1'-EC2' and EC3'-EC4' pairs display binding of three Ca 2 ions similar to that of vertebrate cadherins, domains EC2' and EC3' are joined in a "kinked" orientation by a previously uncharacterized Ca 2 -free linker. Biophysical analysis demonstrates that a construct containing the predicted N-terminal nine EC domains of DN-cadherin forms homodimers with affinity similar to vertebrate classical cadherins, whereas deleting the ninth EC domain ablates dimerization. These results suggest that, unlike their vertebrate counterparts, invertebrate cadherins may utilize multiple EC domains to form intercellular adhesive bonds. Sequence analysis reveals that similar Ca 2 -free linkers are widely distributed in the ectodomains of both vertebrate and invertebrate cadherins.

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Functional Cis-Heterodimers of N- and R-Cadherins

Cited by 182 publications

References 47 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Cadherin Adhesion: Mechanisms and Molecular Interactions

Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca ²⁺ -free interdomain linkers

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Functional Cis-Heterodimers of N- and R-Cadherins

Cited by 182 publications

References 47 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Cadherin Adhesion: Mechanisms and Molecular Interactions

Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca 2+ -free interdomain linkers

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Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca ²⁺ -free interdomain linkers