The Cadherin Resource - Introduction to Cadherins

Introduction to the Cadherin Resource

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CADHERINS

TOPICS
Introduction	Structure
Function	Regulation of Expression and Signal Transduction

INTRODUCTION

Cadherins mediate cell adhesion and play a fundamental role in normal development. They participate in the maintenance of proper cell-cell contacts. Cadherins typically consist of five tandem repeated extracellular domains, a single membrane-spaning segment and a cytoplasmic region. Cadherins depend on calcium for their function: removal of calcium abolishes adhesive activity and renders cadherins vunerable to proteases.

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FUNCTION

Cadherins generally mediate monotypic cell-cell adhesion although heterotypic binding between different cadherin molecules is possible. They act as both receptor and ligand. They are responsible for the selective cell-cell adhesion or cell sorting which is necessary to allocate different cell types to their proper positions during development. They also play a fundamental role in maintaining the integrity of multicellular structures. During embryonic morphogenesis, the expression of multiple members of the cadherin family is spatio-temporally regulated, and correlates with a variety of morphogenetic events that involve cell aggregation or disaggregation.

The role of cadherins in these processes has been demonstrated by the use of anti-cadherin monoclonal antibodies, which, when added to embyonic tissues, cause a severe distortion of structure which results in dissociation of the tissue into small clusters or even single cells.

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STRUCTURE

PDB ID: 1NCG

Molecule: N-Cadherin; Domain: Domain 1 Consisting Of Residues 1 - 108;

The cadherins are synthesized as a precursor polypeptide which requires a series of post-translational modifications (glycosylation, phosphorylation and proteolytic cleavage) to form a protein which is between 723 and 748 amino acids long. The extracelluar domain contains 3-5 internal repeats of approximately 110 amino acids. Repeats 1-3 contain the putative Ca2+ binding site motif DXNDN or DXD, resembling the Ca2+ binding lops of the so-called EF-hand domains. Another high conserved cluster with the motif LDREXXXXYXL is also found with the first three repeats.

The N-terminal 113 amino acids which contain a conserved HAV sequence have been shown to be important in ligand binding and specificity. The extracellular domain is anchored to the cell membrane by a transmembrance domain of approximately 24 amino acids. The short cytoplasmic domain is the most highly conserved region of homology between cadherins and is particularly important for cadherin function

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REGULATION OF EXPRESSION AND SIGNAL TRANSDUCTION

Schematic Representation

Classic cadherin molecules at the cell surface

Cadherins are differentially expressed during development and in adult organs. Since many cell types express multiple cadherin subclasses simultaneously (the combination differs with cell type), it can be inferred that the adhesion properities of individual cells are thus governed by varying the combinations of cadherins. There is also recent evidence to suggest that altered expression of cadherins may be involved in invasion and metastasis of tumour cells.

On the cell surface, cadherins tend to be concentrated at cell-cell junctions. Here they are structurally associated with cortical actin bundles. The cytoplasmic domain has been shown to be associated with cytoplasmic proteins termed catenins. Deletion of the cytoplasmic domain destroys these interactions and also eliminates cadherin function. Recently src, yes, and lyn gene products of the src proto-oncogene family have been found expressed at cell-cell junctions. These kinases may be responsible for cadherin phosphorylation and this raises the possibly that cadherin mediated cell junctions might be used for intercellular signalling

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