ADAM17

ADAM17 Full Name

ADAM metallopeptidase domain 17

ADAM17 Introduction

ADAM17 (A Disintegrin and Metalloproteinase 17), also widely known as TACE (TNF-alpha converting enzyme), is a vital membrane-bound enzyme that plays a central role in cell signaling. It belongs to the ADAM family of metalloproteinases and acts as a molecular "shears" by cleaving the extracellular domains of various transmembrane proteins. This process, known as protein ectodomain shedding, converts membrane-bound precursors into soluble active forms, thereby regulating a wide array of physiological and pathological processes.The architecture of ADAM17 is complex and essential for its catalytic precision. It consists of several distinct regions: an N-terminal signal peptide, a pro-domain that maintains the enzyme in an inactive state, a catalytic domain containing the zinc-binding site, a disintegrin-like domain, a cysteine-rich domain, a transmembrane helix, and a cytoplasmic tail. Unlike many other ADAM family members, the non-catalytic domains of ADAM17 are uniquely configured to assist in substrate recognition and to regulate its trafficking to the cell surface.

Figure 1. Strcuture of ADAM17.

Key Substrates and Shedding Functions

ADAM17 is often called a "sheddase" because it cleaves the extracellular juxtamembrane region of many membrane‑anchored proteins, releasing their soluble ectodomains. Major substrates include: pro‑TNF‑α (release of soluble TNF‑α), TNF receptors (TNFR1 and TNFR2), EGFR ligands such as HB‑EGF, amphiregulin, epiregulin, and TGF‑α, Notch receptors (Notch1 and Notch4), L‑selectin, VCAM‑1, IL‑6 receptor, ACE2, and numerous others. Through these cleavage events, ADAM17 regulates inflammation (by controlling TNF‑α and IL‑6 signaling), cell proliferation and survival (via EGFR ligand shedding), development (Notch pathway), and cell adhesion. The coordinated shedding of ligands and receptors allows ADAM17 to act as a molecular switch that converts membrane‑bound signals into soluble, often paracrine or endocrine, signals. This broad substrate repertoire underscores its pleiotropic physiological roles.

Regulation of ADAM17 Activity

ADAM17 activity is tightly controlled at multiple levels to prevent excessive or inappropriate shedding. First, the prodomain must be removed by proprotein convertases; unprocessed ADAM17 is inactive. Second, ADAM17 is often localized in specific membrane microdomains (lipid rafts) and its trafficking to the cell surface is regulated by the iRhom proteins (iRhom1 and iRhom2), which are essential co‑factors for ADAM17 maturation and transport. Third, ADAM17 can be rapidly activated by various stimuli, including phorbol esters, growth factors, GPCR agonists, and cellular stress, through mechanisms involving phosphorylation by MAP kinases, protein kinase C (PKC), and the recruitment of the metalloproteinase to the substrate. Fourth, ADAM17 can be inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs), particularly TIMP‑3, which forms a tight complex with the catalytic domain. Dysregulation of these control mechanisms contributes to pathological conditions such as chronic inflammation and tumor progression.

Alternate Names for ADAM17

ADAM17; ADAM metallopeptidase domain 17; CSVP; TACE; NISBD; ADAM18; CD156B; NISBD1; disintegrin and metalloproteinase domain-containing protein 17; TNF-alpha convertase