29.2:
Structure of Cadherins
Cadherins are a superfamily of calcium-dependent cell adhesion molecules or CAMs .
All cadherins have a basic structure comprising a small C-terminal cytosolic domain, a single transmembrane domain, and multiple extracellular cadherin or EC domains.
These EC domains are linked to each other by flexible hinge regions, each with three calcium-binding pockets.
When calcium ions bind, the cadherin becomes rigid, enabling cis– and trans-binding to other cadherins.
In cis-binding, cadherins on the same cell can bind to each other forming clusters, while the interaction of the EC domains of cadherins on adjacent cells results in trans-binding.
The N-terminal EC domain, furthest from the membrane, called EC1, has a knob and pocket structure. During trans-binding, the knob of one EC1 fits into the pocket of another EC1 on the adjacent cell.
This makes cadherins of one type preferentially bind cadherins of the same type, a homophilic binding.
Although the interaction between a single pair of cadherins is relatively weak, the cadherin clusters can form a collectively strong trans-binding. Such complexes form anchoring cell junctions.
29.2:
Structure of Cadherins
The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins” is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins arises from multiple cadherin genes in the genome and alternative RNA splicing during transcription.
Cadherins in Cell Junctions
Cadherins are transmembrane proteins with multiple extracellular binding domains. Their cytosolic domain binds linker proteins that connect to the cytoskeleton. Cadherins cluster together on the plasma membrane by cis-binding, forming large, multi-protein complexes called cell junctions. Whereas classical cadherins such as E-cadherin form adherens junctions, non-classical cadherins like desmoglein and desmocollin form desmosomal junctions. These cell junctions function to hold the cells together and provide mechanical strength to tissues, such as the epithelium.
Clinical Significance of Cadherins
Cadherins play an essential role in cell adhesion, tissue formation, and intercellular communication. Consequently, any change in their structure, expression, and stability can manifest into clinical conditions. When the cells lose contact with neighboring cells, they can break free from the tissue and invade other tissues. Loss of cell adhesion due to mutations in cadherin genes is associated with the malignancy of tumors, such as those seen in breast malignant cells. Pathogens also use cadherins as receptors to attach and invade the host cell. For example, the cadherin CDHR3 is highly expressed in the lung epithelium and is used as a receptor by the class-C rhinovirus (RV-C) that causes the common cold.
Suggested Reading
- Shapiro, Lawrence, and William I. Weis. "Structure and biochemistry of cadherins and catenins." Cold Spring Harbor perspectives in biology 1.3 (2009): a003053.