ADAMTS4

A disintegrin and metalloproteinase with thrombospondin motifs 4 is an is_associated_with::enzyme that in humans is encoded by the ADAMTS4 is_associated_with::gene.

This gene encodes a member of the is_associated_with::ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a is_associated_with::metalloproteinase domain, a is_associated_with::disintegrin-like domain, and a is_associated_with::thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of is_associated_with::C-terminal TS motifs, and some have unique C-terminal domains. The is_associated_with::enzyme encoded by this gene lacks a C-terminal TS motif. It can degrade is_associated_with::aggrecan, a major proteoglycan of cartilage, is_associated_with::brevican, a brain-specific is_associated_with::extracellular matrix protein, is_associated_with::neurocan and is_associated_with::versican. The cleavage of aggrecan and brevican suggests key roles of this enzyme in arthritic disease and in the is_associated_with::central nervous system, potentially, in the progression of is_associated_with::glioma.

Structure
ADAMTS4 is the shortest known is_associated_with::ADAMTS, lacking the C-terminal domain and is the only non-glycosylated is_associated_with::ADAMTS. It also only has one is_associated_with::thrombospondin type 1 motif (TSR), whereas all the other ADAMTS have two or more TSRs. The TSR is important for binding of the enzyme to the is_associated_with::extracellular matrix and hence its substrate specificity. Adjacent to the C-terminal TSR is a is_associated_with::disintegrin-like domain, a is_associated_with::cysteine-rich region that stacks against the active-site of the is_associated_with::enzyme when in its final folded tertiary structure.

Function
ADAMTS4 is capable of cleaving all the large is_associated_with::chondroitin sulfate is_associated_with::hyaluronan-binding proteoglycans (CSPGs), including is_associated_with::aggrecan, is_associated_with::brevican, is_associated_with::neurocan and is_associated_with::versican. Like is_associated_with::ADAMTS5, it can be effectively inhibited by tissue inhibitor of is_associated_with::metalloproteinase-3 (is_associated_with::TIMP3) and this inhibition can be enhanced in the presence of is_associated_with::aggrecan. In addition to is_associated_with::TIMP3, it can also be inhibited by calcium is_associated_with::pentosan polysulfate.

ADAMTS4 is expressed in is_associated_with::ovary, is_associated_with::spinal cord, is_associated_with::adrenal cortex, is_associated_with::ciliary ganglion, is_associated_with::trigeminal ganglion, is_associated_with::brain, is_associated_with::retina, is_associated_with::pancreas (islets), fetal is_associated_with::lung, is_associated_with::breast myoepithelial cells, is_associated_with::tendon and is_associated_with::cartilage.

Clinical Significance
ADAMTS4 (and is_associated_with::ADAMTS5) are the major is_associated_with::proteinases responsible for the degradation of is_associated_with::proteoglycans in is_associated_with::articular cartilage in is_associated_with::osteoarthritis. Which of these aggrecanases is more important in is_associated_with::cartilage degradation appears to be species-specific, with ADAMTS4 more important in human disease (but is_associated_with::ADAMTS5 more important in is_associated_with::mouse models of is_associated_with::osteoarthritis).

Alternative names

 * Aggrecanase-1 (initial name reflecting its ability to cleave is_associated_with::aggrecan)