Biochemistry and physiological functions of ADAMTS7 metalloprotease

Abstract

Here, we provide a comprehensive review of current findings concerning the biochemistry and physiological functions of ADAMTS7, a metalloprotease that is known to interact with cartilage oligomeric matrix protein, progranulin, and alpha2-macroglobulin. Such broad substrate specificity and potentially diverse physiological functions make ADAMTS7 an interesting enzyme to study. ADAMTS7 has been shown to play a role in the pathogenesis of arthritis and disc disorders. More recently, the ADAMTS7 locus is identified to have a strong association with coronary atherosclerotic disease. However, the role of ADAMTS7 in the development of atherosclerosis is yet to be determined. The development of an easy and high throughput assay for ADAMTS7 activity and appropriate animal models will allow us to uncover the novel mechanisms of coronary arterial disease.

Keywords: ADAMTS7; Cardiovascular Disease; Smooth Muscle Cell; Structure-Function; Substrate Specificity.

Figure1

Schematic structure and domain organization of ADAMTS7. Human ADAMTS7 consists of a conserved signal peptide, prodomain, and metalloprotease domain. The C-terminus of ADAMTS7 contains a disintegrin domain, the first thrombospondin type 1 repeat (TSP1), Cys-rich domain, and 7 additional TSP1 repeats interspaced with two spacer domains. The second spacer domain is also a mucin-like domain.

Figure2

Regulation of ADAMTS7 expression and its potential role in VSMCs. COMP is associated with vascular smooth muscle cells via binding to the α7β1 integrin and is cleaved by ADAMTS7. This proteolytic cleavage is regulated by several factors: inflammatory cytokines such as TNFα, IL-1β, TGF- β; growth factor PDGF-BB; the reactive oxygen species H2O2; microRNA miR-29a/b; and progranulin (PGN), and α2-MG. Cleavage of COMP has the highlighted physiological consequences such as cell proliferation and migration.

Figure3

Schematic structure and domain organization of COMP. A. Human COMP comprises a pentamerizing domain, four EGF-like domains, seven type 3 repeats, and a globular domain. B. A schematic diagram illustrates the pentameric form of COMP and potential proteolytic cleavage sites by ADAMTS7.

Figure4

Schematic domain organization and proteolytic processing of PGRN. Boxed letters indicate individual granulin domains. Scissors denote the elastase cleavage site and asterisks are the linker regions where proteolytic cleavage also takes place. However, the protease that releases granulins A and B has not been conclusively identified. The amino acid sequence of granulin A is shown at the bottom as an example. Cysteines are underlined. Numbers below the sequence denote approximate positions of granulin domains in relation to full-length human progranulin.

Figure5

Schematic representation of conformational change and protease trapping processes of α2-MG. Once a proteolytic enzyme such as ADAMTS7 (AT7) is absorbed to α2-MG, rapid conformational changes of the α2-MG-AT7 complex occur. This process results in either an activation or an inhibition of the protease- α2-MG complex, depending on the protease bound. In the case of AT7, α2-MG trapping results in inactivation of AT7 proteolytic activity toward other substrates.