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Disintegrin domains are small, cysteine-rich protein modules approximately 70–100 amino acids long that occur in a family of venom proteins and in larger human proteins such as members of the ADAM (a disintegrin and metalloprotease) and ADAMTS (ADAM with thrombospondin motifs) families. Their defining feature is an exposed integrin-binding loop that can carry short recognition motifs, most famously the tripeptide RGD, but also variants such as KGD, MLD, and REDV. The motif and surrounding residues determine binding to specific integrins (for example, RGD-containing disintegrins commonly block αvβ3 and α5β1, while KGD-type disintegrins preferentially inhibit αIIbβ3).

Biological roles: In venom, disintegrin domains act as potent anti-adhesive toxins, preventing platelet aggregation and dispersing prey. In humans and other vertebrates, disintegrin domains are present in ADAM and related proteins and regulate cell adhesion, migration, angiogenesis, fertilization, and signaling. In ADAMs, the disintegrin domain sits near the amino terminus and can be followed by a metalloprotease domain; in some proteins the domain is “disintegrin-like” and lacks the canonical RGD motif, yet retains integrin-binding activity.

Evolution and structure: The domain is stabilized by multiple disulfide bonds formed by conserved cysteine residues. It has diversified through gene duplication and domain shuffling, contributing to venom diversity and to the functional versatility of ADAM family proteins.

Research and applications: Disintegrin domains are used as tools to study integrin function and have inspired anti-adhesion therapeutic strategies. Their high potency and selectivity, however, pose challenges for clinical use, and several investigational agents targeting integrins have pursued disintegrin-based designs.

See also: Integrin, Disintegrin, ADAM (protein family), ADAMTS.