Adhesion Molecules in the Nervous System: Structural Insights into Function and Diversity

Shapiro, Lawrence; Love, James M.; Colman, David

doi:10.1146/annurev.neuro.29.051605.113034

Cited by 187 publications

(166 citation statements)

References 113 publications

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“…In the case of CDH2/N-cadherin, this is via sequential binding of b-catenin to a-catenin and then through intermediates to actin. 15,27,28 N-cadherin is required for critical brain processes, including long-term potentiation, pre-to post-synaptic adhesion, dendritic spine elongation -thereby regulating glutamate receptor trafficking and neuronal migration. [29][30][31][32] A bioinformatic prediction of the multiple functional associations for CDH2 is provided in Supplementary Figure 2.…”

Section: Resultsmentioning

confidence: 99%

“…12,13 CDH2 belongs to the cadherin gene family of cell-cell adhesion molecules, which function in early brain morphogenesis, synaptogenesis and synaptic plasticity, including synaptic vesicle trafficking in glutamatergic neurons. [14][15][16][17] Other cadherin genes, including CDH8, CDH9 and CDH10, have recently been implicated in the etiology of autism spectrum disorders, which may also be characterized by repetitive and compulsive behaviors. [18][19][20] We hypothesized that variants in the human ortholog CDH2 could confer susceptibility to OCD and OCD spectrum disorders such as TD.…”

Section: Introductionmentioning

confidence: 99%

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Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

et al. 2013

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The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N ¼ 1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P ¼ 0.014, OR ¼ 6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

et al. 2013

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“…Because many mammalian adhesion proteins including cadherins, integrins, and neurexins require divalent cations for proper function (18,19), we analyzed Brpt1.5 by AUC in the presence of Ca 2ϩ , Sr 2ϩ , Mg 2ϩ , Mn 2ϩ , Ni 2ϩ , Co 2ϩ , and Zn 2ϩ . Interestingly, Brpt1.5 formed dimers only in the presence of Zn 2ϩ ( Fig.…”

Section: Solutionmentioning

confidence: 99%

“…Taken together, the CD and AUC results for Brpt1.5 and Brpt2.5 indicate that the G5 domains of Aap self-assemble in a modular fashion upon Zn 2ϩ binding. The presence of tandem domain repeats and dependence upon a divalent cation for adhesion are reminiscent of calciumdependent adhesion by mammalian cadherins (19).…”

Section: Solutionmentioning

confidence: 99%

A zinc-dependent adhesion module is responsible for intercellular adhesion in staphylococcal biofilms

Conrady

Brescia

Horii

et al. 2008

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

200

285

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Hospital-acquired bacterial infections are an increasingly important cause of morbidity and mortality worldwide. Staphylococcal species are responsible for the majority of hospital-acquired infections, which are often complicated by the ability of staphylococci to grow as biofilms. Biofilm formation by Staphylococcus epidermidis and Staphylococcus aureus requires cell-surface proteins (Aap and SasG) containing sequence repeats known as G5 domains; however, the precise role of these proteins in biofilm formation is unclear. We show here, using analytical ultracentrifugation (AUC) and circular dichroism (CD), that G5 domains from Aap are zinc (Zn 2؉ )-dependent adhesion modules analogous to mammalian cadherin domains. The G5 domain dimerizes in the presence of Zn 2؉ , incorporating 2-3 Zn 2؉ ions in the dimer interface. Tandem G5 domains associate in a modular fashion, suggesting a ''zinc zipper'' mechanism for G5 domain-based intercellular adhesion in staphylococcal biofilms. We demonstrate, using a biofilm plate assay, that Zn 2؉ chelation specifically prevents biofilm formation by S. epidermidis and methicillin-resistant S. aureus (MRSA). Furthermore, individual soluble G5 domains inhibit biofilm formation in a dose-dependent manner. Thus, the complex threedimensional architecture of staphylococcal biofilms results from the self-association of a single type of protein domain. Surface proteins with tandem G5 domains are also found in other bacterial species, suggesting that this mechanism for intercellular adhesion in biofilms may be conserved among staphylococci and other Gram-positive bacteria. Zn 2؉ chelation represents a potential therapeutic approach for combating biofilm growth in a wide range of bacterial biofilm-related infections.bacterial pathogenesis ͉ G5 domain ͉ Aap ͉ chelation ͉ Staphylococcus

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“…hair cell | tip link | hair cell | PCDH21 | PCDH24 T he organization of cells into tissues and organs depends on cadherin molecules that regulate such diverse processes as cell adhesion, synapse formation, and the development and function of sensory cells in the inner ear and retina (1)(2)(3)(4). The defining feature of the cadherin superfamily is the extracellular cadherin (EC) domain, which occurs in varying repetitions in all cadherins.…”

mentioning

confidence: 99%

Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members

Elledge

Kaźmierczak

Clark³

et al. 2010

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

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The cadherin superfamily encodes more than 100 receptors with diverse functions in tissue development and homeostasis. Classical cadherins mediate adhesion by binding interactions that depend on their N-terminal extracellular cadherin (EC) domains, which swap Nterminal β-strands. Sequence alignments suggest that the strandswap binding mode is not commonly used by functionally divergent cadherins. Here, we have determined the structure of the EC1-EC2 domains of cadherin 23 (CDH23), which binds to protocadherin 15 (PCDH15) to form tip links of mechanosensory hair cells. Unlike classical cadherins, the CDH23 N terminus contains polar amino acids that bind Ca 2+ . The N terminus of PCDH15 also contains polar amino acids. Mutations in polar amino acids within EC1 of CDH23 and PCDH15 abolish interaction between the two cadherins. PCDH21 and PCDH24 contain similarly charged N termini, suggesting that a subset of cadherins share a common interaction mechanism that differs from the strand-swap binding mode of classical cadherins.T he organization of cells into tissues and organs depends on cadherin molecules that regulate such diverse processes as cell adhesion, synapse formation, and the development and function of sensory cells in the inner ear and retina (1-4). The defining feature of the cadherin superfamily is the extracellular cadherin (EC) domain, which occurs in varying repetitions in all cadherins. Based on sequence homology and domain structure, cadherins are divided into subfamilies including the classical cadherins, desmosomal cadherins, seven transmembrane cadherins, and protocadherins. Classical cadherins and desmosomal cadherins are the best-studied superfamily members and have well-documented roles in mediating cell adhesion and the formation of desmosomes, respectively (1-4). The function and adhesive properties of other cadherin superfamily members are less well studied.Crystallographic and biochemical studies have provided insights into the structure of cadherin extracellular domains and the mechanism that mediates adhesion between classical cadherins (5-13). The EC domain forms a protein module of the Ig-like fold consisting of seven β-strands that are arranged as two opposed β-sheets. The Nand C termini reside on opposite ends of the EC domain, facilitating the formation of tandem repeats. The connections between successive EC domains are rigidified by coordination of three Ca 2+ ions, which is mediated by amino acids that are conserved in all cadherins (5,9,14). Adhesion specificity resides in the EC1 domains. The crystallographic structures show that the adhesive binding interface is formed by "swapping" of the amino-terminal β-strands of opposite EC1 domains, whereby the strand of one monomer replaces the strand of the other. Critical for this interaction are the side chains of conserved Trp residues, which fit into hydrophobic pockets on the EC1 domain of the binding partner (5,8,10).Recent findings suggest that the formation of cadherin adhesion complexes is a multistep process, where cadherins ...

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Adhesion Molecules in the Nervous System: Structural Insights into Function and Diversity

Cited by 187 publications

References 113 publications

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

A zinc-dependent adhesion module is responsible for intercellular adhesion in staphylococcal biofilms

Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members

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