TIMP3

TIMP3, or tissue inhibitor of metalloproteinases 3, is a secreted glycoprotein that belongs to the TIMP family, which regulate extracellular matrix remodeling by inhibiting metalloproteinases. The TIMP3 gene is located on chromosome 22q12.3. The protein is widely expressed, with notable expression in the eye and connective tissues, and it is predominantly localized in the extracellular matrix where it binds to basement membranes and proteoglycans.

Functionally, TIMP3 inhibits a broad spectrum of matrix metalloproteinases, including several collagenases and gelatinases, thereby limiting extracellular matrix degradation. It also inhibits certain members of the ADAM family proteases, such as ADAMTS-4 and ADAMTS-5, and can influence ADAM17 activity in some contexts, contributing to regulation of angiogenesis and inflammation.

Clinical significance is highlighted by mutations in TIMP3 causing Sorsby fundus dystrophy, an autosomal dominant inherited macular dystrophy characterized by retinal degeneration and choroidal neovascularization. Beyond this specific disorder, TIMP3 has been investigated in relation to age-related macular degeneration and other diseases involving extracellular matrix remodeling; however, its precise contributions appear complex and context-dependent.

Structure and mechanism summaries note that the TIMP3 protein is a secreted glycoprotein of roughly two hundred amino acids, with distinct domains that form inhibitory complexes with metalloproteinase active sites. Its retention in the extracellular matrix is reinforced by interactions with matrix components, helping to localize its protease-inhibitory activity to the extracellular milieu.