This gene encodes a member of the matrix metalloproteinase (MMP) family of proteins. These proteins are involved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Proteolysis at different sites on this protein results in multiple active forms of the enzyme with distinct N-termini. MMP-8 also called neutrophil collagenase or collagenase 2, is characterized (like other collagenase) for its abilities to cleave triple-helical regions of interstitial collagnes (types I, II, and III) at a site about three-fourths away from the N-terminus. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Alternative splicing results in multiple transcript variants.[1]
To see
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Structure
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Thanks to X-ray crystallography, the structure of 2OY4 has been solved with 1,7 Å resolution. This enzyme consists of and .
Pocket interaction
Ca2+
The active site of the enzyme is composed by two Gly residues (169 and 171) next to two Asp residues (137 and 173).
This enzyme binds 3 CA ions per subunit.
maintain a Zn2+ atom coordinated with three water molecules. One of them is as well bound to the Glu residue thanks to a hydrogen bond. The second Zn2+ atom is not involved in the active site. At first, the Gly 206 residue of the substrate binds the active site thanks to the Zn2+ atom. When it binds it takes the place of unstable water molecules and establishes stabilizing interactions with the active site thanks to its C terminal part. Then, the Ala 182 residue of the enzyme makes a hydrogen bond with the NH group of the substrate: this allows the substrate to enter the cavity of the catalytic site. The rest of the protein is stabilized by 4 hydrogen bonds with the amino acid located in the cavity.
Zn2+
The active site of the enzyme is composed by one Asp residue (149) next to three His residues (147, 162 and 175).
This enzyme binds 2ZN ions per subunit.
maintain a Zn2+ atom coordinated with three water molecules. One of them is as well bound to the Glu residue thanks to a hydrogen bond. The second Zn2+ atom is not involved in the active site. At first, the Gly 206 residue of the substrate binds the active site thanks to the Zn2+ atom. When it binds it takes the place of unstable water molecules and establishes stabilizing interactions with the active site thanks to its C terminal part. Then, the Ala 182 residue of the enzyme makes a hydrogen bond with the NH group of the substrate: this allows the substrate to enter the cavity of the catalytic site. The rest of the protein is stabilized by 4 hydrogen bonds with the amino acid located in the cavity.
The conserved cysteine present in the cysteine-switch motif (89-96) binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.
Function
Like all the MMPs, MMP8 is secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases. Indeed, it can't be activated without removal of the .
cleave the helical collagen molecule at a single Gly-Ile/Leu bond in each alpha-chain of the molecule. The cleavage 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[3]
metalloendopeptidase activity = mechanism in which water acts as a nucleophile, one or two metal ions hold the water molecule in place, and charged amino acid side chains are ligands for the metal ions.[4]
Disease
Relevance
Structural highlights
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