A disintegrin and metalloproteinase domain-containing protein 10 and A disintegrin and metalloproteinase domain-containing protein 17 (ADAM10, ADAM17)

ADAM10 and ADAM17 are zinc-dependent metalloproteases that function as sheddases, responsible for the proteolytic cleavage (ectodomain shedding) of numerous transmembrane proteins, leading to activation or modulation of growth factor, cytokine, and receptor signaling. ADAM17, also called TACE (Tumor necrosis factor-alpha converting enzyme), is essential for the release of active TNF-alpha and several epidermal growth factor receptor (EGFR) ligands, impacting cell proliferation, survival, and inflammation. ADAM10 similarly regulates Notch and ephrin signaling pathways and is involved in neural development. Both proteins share structural homology but regulate distinct and overlapping substrate repertoires, are tightly regulated at the cell surface, and are implicated in cancer, inflammatory disorders, neurodegeneration, and viral pathogenesis (notably by enhancing SARS-CoV-2 entry and syncytia formation). Therapeutic targeting of ADAM10/ADAM17 presents challenges due to their ubiquitous expression, vital developmental roles, and broad substrate specificity.

Other names

A disintegrin and metalloproteinase 10A disintegrin and metalloproteinase 17TACE

Direct inhibition of catalytic activity (small molecules, biologicals, or endogenous inhibitors bind the metalloprotease domain and block substrate cleavage) Modulation of substrate recognition or maturation (interference with regulatory partners or prodomain)