Sandbox Reserved 1125: Difference between revisions
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MMP-8 is secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases. Indeed, it can't be activated without removal of the activation peptide. But recent evidences suggest that this protease activation is blocked by the formation of an intramolecular complex between the propeptide domain on the Cysteine residue (Cys91) and essential zinc atom in the catalytic domain. It is called the ''Cysteine-switch''. This discovery is unprecedented in enzymology and offers the opportunity for multiple modes of physiological activation of MMP-8. Moreover, since conditions in different cells and tissues may match those necessary to effect one of these activation modes for a given MMP, this may offer metabolic flexibility in the control of MMP activation.<ref>PMID:2164689</ref> | MMP-8 is secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases. Indeed, it can't be activated without removal of the activation peptide. But recent evidences suggest that this protease activation is blocked by the formation of an intramolecular complex between the propeptide domain on the Cysteine residue (Cys91) and essential zinc atom in the catalytic domain. It is called the ''Cysteine-switch''. This discovery is unprecedented in enzymology and offers the opportunity for multiple modes of physiological activation of MMP-8. Moreover, since conditions in different cells and tissues may match those necessary to effect one of these activation modes for a given MMP, this may offer metabolic flexibility in the control of MMP activation.<ref>PMID:2164689</ref> | ||
To express collagenolytic activity, MMP-8 needs to have both the catalytic and hemopexin domains. The linker peptide can position the hemopexin domain in such a way that it bends over the active site of the catalytic domain. But understanding how the Hemopexin domain assists in the cleavage of collagen is elusive.<ref>PMID:15257288</ref> Thus, the collagen would be captured between these two domains. However, the active site cannot accommodate the entire triple helix in a native state. The linker peptide would, by means of its collagen-like conformation, change the quaternary structure of the captured collagen. Interactions between proline residues of the collagenase and a specific region of the collagen would generate a “proline zipper,” resulting in destabilization of the cleavage site area of the collagen. After destabilization, one chain of the triple helix fits in the <scene name='71/719866/Catalytic_site/ | To express collagenolytic activity, MMP-8 needs to have both the catalytic and hemopexin domains. The linker peptide can position the hemopexin domain in such a way that it bends over the active site of the catalytic domain. But understanding how the Hemopexin domain assists in the cleavage of collagen is elusive.<ref>PMID:15257288</ref> Thus, the collagen would be captured between these two domains. However, the active site cannot accommodate the entire triple helix in a native state. The linker peptide would, by means of its collagen-like conformation, change the quaternary structure of the captured collagen. Interactions between proline residues of the collagenase and a specific region of the collagen would generate a “proline zipper,” resulting in destabilization of the cleavage site area of the collagen. After destabilization, one chain of the triple helix fits in the <scene name='71/719866/Catalytic_site/4'>active site</scene> of MMP-8 and the carbonyl group of the peptide bond coordinates with it.<ref>PMID:17185359</ref> This displaces the water molecule from the zinc atom. The peptide hydrolysis is assisted by the carboxyl group of the glutamate, which serves as a general base to draw a proton from the displaced water molecule, thereby facilitating the nucleophilic attack of the water molecule on the carbonyl carbon of the peptide scissile bond. A pocket to the right of the active-site zinc, called the specificity pocket or <scene name='71/719866/S1prime_pocket/1'>S1' pocket</scene>, accommodates the side chain of the substrate residue, which becomes the new N-terminus after cleavage. The sizes of the S1′ pocket vary among the MMPs, and this is one of the major determining factors of substrate specificity.<ref>PMID:12730128</ref> | ||
The cleavage is at Gly775–Ile776 or Leu776 in each alpha-chain of the collagen molecule.<ref>PMID:9094424</ref> The cleavage, taking place at neutral pH, generates fragments that spontaneously lose their helical conformation, denature to gelatin, and become soluble. The gelatin is then susceptible to attack by gelatinases and other proteases.<ref>[http://www.ebi.ac.uk/interpro/entry/IPR028709 "Neutrophil collagenase"]</ref> | The cleavage is at Gly775–Ile776 or Leu776 in each alpha-chain of the collagen molecule.<ref>PMID:9094424</ref> The cleavage, taking place at neutral pH, generates fragments that spontaneously lose their helical conformation, denature to gelatin, and become soluble. The gelatin is then susceptible to attack by gelatinases and other proteases.<ref>[http://www.ebi.ac.uk/interpro/entry/IPR028709 "Neutrophil collagenase"]</ref> | ||
