Matrix metalloproteinases and collagen catabolism

Abstract

The matrix metalloproteinase (MMP)/matrixin family has been implicated in both normal tissue remodeling and a variety of diseases associated with abnormal turnover of extracellular matrix components. The mechanism by which MMPs catabolize collagen (collagenolysis) is still largely unknown. Substrate flexibility, MMP active sites, and MMP exosites all contribute to collagen degradation. It has recently been demonstrated that the ability to cleave a triple helix (triple-helical peptidase activity) can be distinguished from the ability to cleave collagen (collagenolytic activity). This suggests that the ability to cleave a triple helix is not the limiting factor for collagenolytic activity-the ability to properly orient and potentially destabilize collagen is. For the MMP family, the catalytic domain can unwind and cleave a triple-helical structure, while the C-terminal hemopexin-like domain appears to be responsible for properly orienting collagen and destabilizing it to some degree. It is also possible that exosites within the catalytic and/or C-terminal hemopexin-like domain may exclude some MMPs from cleaving collagen. Overall, it appears that many proteases of distinct mechanisms possess triple-helical peptidase activity, and that convergent evolution led to a few proteases possessing collagenolytic activity. Proper orientation and distortion of the triple helix may be the key factor for collagenolysis.

Solution Structure of an ABC Collagen Heterotrimer Reveals a Single-register Helix Stabilized by Electrostatic Interactions

“…It has been reported that local fluctuations in the triple helical stability may play a role in the interactions of collagens and other proteins, such as matrix metalloproteases (43). So far, the imino acid content of a particular sequence stretch has been the main factor used in such considerations, but it is known that collagenase labile stretches contain a very low content of charged residues (44,45). The results presented here suggest that the lack of salt bridges in those regions may provide a complementary destabilization strategy.…”

The Role of Collagen Charge Clusters in the Modulation of Matrix Metalloproteinase Activity

“…Several features of the cleavage site have been shown to contribute to MMP specificity, including the distribution of secondary amino acids (Pro and Hyp), dynamics of the peptide backbone, and overall lack of charged residues (with the primary exception of the P 5 Ј and P 8 Ј subsites) (1,5,24,31). The interaction of MMPs with triple helices encompasses at least the P 13 -P 17 Ј subsites (26,27,29,60).…”

“…Features of the MMP cleavage site in interstitial collagens have been investigated through a variety of approaches, including (a) kinetic analyses of MMP hydrolysis of native and mutant collagens and triple-helical peptide (THP) models of collagen, (b) biophysical studies (NMR spectroscopy and x-ray crystallography) of THPs, and (c) molecular dynamics simulations of triple helices (6 -30). It has been noted that, although collagen has a significant distribution of charged residues, relatively few are found at the site of MMP hydrolysis (5,31). More specifically, the overall 25-amino acid residue region surrounding the site of hydrolysis (subsites P 13 -P 12 Ј) contains a maximum of two charged residues (Glu in the P 8 subsite of the ␣1(II) chain, Arg in the P 5 Ј subsite of the ␣1(I) and ␣1(II) chains, and Arg in the P 8 Ј subsite of the ␣1(III) chain).…”

The Hemopexin and O-Glycosylated Domains Tune Gelatinase B/MMP-9 Bioavailability via Inhibition and Binding to Cargo Receptors

“…Collagenolysis by interstitial collagenase is dependent on the hemopexin domain and linker peptide (12). Gelatinolysis by gelatinases is more than 100-fold enhanced by the gelatin-binding fibronectin domain (13).…”