Structure of Cadherins

Cadherins are calcium-dependent cell adhesion molecules with three key structural components: a cytosolic domain at the C-terminal end, a single transmembrane domain, and multiple extracellular cadherin (EC) domains. The EC domains are connected by flexible hinge regions, each containing three calcium-binding pockets. This architecture enables cadherins to function as cell adhesion molecules when calcium ions bind and stabilize the structure.

Calcium ions bind to three pockets within the flexible hinge regions connecting EC domains, causing the cadherin structure to become rigid. This rigidity enables cadherins to engage in both cis-binding, where cadherins on the same cell cluster together, and trans-binding, where EC domains from adjacent cells interact. Without calcium, cadherins cannot achieve the structural stability necessary for these binding interactions.

Homophilic binding occurs when cadherins of one type preferentially bind to cadherins of the same type. The N-terminal EC1 domain has a knob-and-pocket structure where the knob of one EC1 fits into the pocket of another EC1 on an adjacent cell. This type-specific binding ensures that cells expressing the same cadherin type preferentially adhere to each other, which is crucial for tissue organization and cell sorting.

Although individual cadherin-to-cadherin interactions are relatively weak, cadherins cluster together on the plasma membrane through cis-binding, forming large multi-protein complexes. These cadherin clusters collectively generate strong trans-binding between adjacent cells, creating anchoring cell junctions. The cumulative strength of multiple cadherin interactions provides the mechanical stability needed to hold tissues together.

Classical cadherins, such as E-cadherin, N-cadherin, and P-cadherin, share sequence and structural similarities and form adherens junctions. Non-classical cadherins, including desmoglein and desmocollin, form desmosomal junctions and are often involved in cell signaling. This diversity arises from multiple cadherin genes in the genome and alternative RNA splicing during transcription, allowing cells to express different cadherin types for specialized functions.

The cytosolic domain of cadherins binds to linker proteins that connect to the cytoskeleton, anchoring the cell adhesion machinery to the internal cellular structure. This connection allows cadherins to transmit mechanical forces and maintain tissue integrity. Through these linker proteins, cadherins integrate cell-cell adhesion with the structural framework of the cell.

Loss of cadherin expression or function disrupts cell adhesion, allowing cells to break free from tissues and invade other areas, a hallmark of malignancy. Mutations in cadherin genes are associated with tumor progression in breast cancer and other malignancies. Additionally, pathogens exploit cadherins as receptors; for example, class-C rhinovirus uses CDHR3 cadherin expressed in lung epithelium to attach and invade host cells.