Ectodomains

Ectodomains are the extracellular portions of cell-surface or secreted proteins that reside outside the cell membrane. They commonly mediate ligand binding, cell–cell interactions, receptor dimerization, and the initiation of signaling cascades. Ectodomains are modular and frequently contain domains such as immunoglobulin-like folds, cadherin repeats, EGF-like repeats, fibronectin type III repeats, or leucine-rich repeats. They are often heavily glycosylated and stabilized by disulfide bonds, which contribute to their structural and binding properties.

Many ectodomains undergo regulated proteolytic processing. Ectodomain shedding, typically carried out by metalloproteases of the ADAM family, releases a soluble ectodomain into the extracellular space and leaves a membrane-tetached stub that can be further processed by intramembrane proteases in a process called regulated intramembrane proteolysis (RIP). This processing can generate intracellular signaling fragments that influence transcription or cytoplasmic signaling. Notable examples include the Notch receptor, where ADAM-mediated shedding followed by gamma-secretase cleavage releases a Notch intracellular domain that modulates gene expression, and the amyloid precursor protein (APP), where shedding and subsequent gamma-secretase activity release Aβ peptides and the intracellular domain.

Ectodomains play central roles in development, immunity, tissue homeostasis, and disease. Soluble ectodomains can act as decoys for ligands or as signaling mediators, and dysregulated shedding has been linked to cancer, neurodegeneration, and inflammatory disorders. Structurally, their domain composition and post-translational modifications determine binding specificity and functional outcomes, making ectodomains common targets for therapeutic antibodies and biomarkers.