Sandbox Reserved 1125: Difference between revisions
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The difference between this classification and EC 3.4.24.7 is that this enzyme cleaves type III collagen more slowly than type I. | The difference between this classification and EC 3.4.24.7 is that this enzyme cleaves type III collagen more slowly than type I. | ||
(On [http://www.brenda-enzymes.org/enzyme.php?ecno=3.4.24.34&UniProtAcc=P22894&OrganismID=2681 BRENDA], you can find all pieces of information about the | (On [http://www.brenda-enzymes.org/enzyme.php?ecno=3.4.24.34&UniProtAcc=P22894&OrganismID=2681 BRENDA], you can find all pieces of information about the MMP-8 enzyme like, for example, a list of different substrates or inhibitors) | ||
== Structure and domains == | == Structure and domains == | ||
MMP-8 is composed of several domains: a propeptide, a catalytic domain, a hinge region, and a C-terminal | MMP-8 is composed of several domains: a propeptide, a catalytic domain, a hinge region, and a C-terminal hemopexin-like domain.<ref name="Pdf">[https://www.google.fr/url?sa=t&rct=j&q=&esrc=s&source=web&cd=5&cad=rja&uact=8&ved=0ahUKEwipxN6imszKAhVCPxoKHR5QDC4QFghFMAQ&url=http%3A%2F%2Fwww.springer.com%2Fcda%2Fcontent%2Fdocument%2Fcda_downloaddocument%2F9780896036680-c2.pdf%3FSGWID%3D0-0-45-494797-p173728219&usg=AFQjCNHRfP-tVHWXP2ljUTd3MjjhObqnCA&sig2=6RnjnFvqo7PVhxvSDDsOlw Substrate specificity of MMPs]</ref>. | ||
=== Propeptide === | === Propeptide === | ||
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=== Catalytic domain === | === Catalytic domain === | ||
Thanks to X-ray crystallography, the catalytic domain structure has been solved with 1,7 Å resolution (2OY4).This domain is composed of 157 residues, from Met86 to Gly242, organized in <scene name='71/719866/Helixes/4'>three alpha helixes</scene> and <scene name='71/719866/Sheets/3'>five beta sheets</scene>.The protein folding and especially the zinc environment of the collagenase catalytic domain is very close to the astacins and the snake venom metalloproteinases. The catalytic domain alone has proteolytic activity against other protein substrates and synthetic substrates.<ref name="X-ray">PMID:8137810</ref> | Thanks to X-ray crystallography, the catalytic domain structure has been solved with 1,7 Å resolution (PDB ID : 2OY4).This domain is composed of 157 residues, from Met86 to Gly242, organized in <scene name='71/719866/Helixes/4'>three alpha helixes</scene> and <scene name='71/719866/Sheets/3'>five beta sheets</scene>.The protein folding and especially the zinc environment of the collagenase catalytic domain is very close to the astacins and the snake venom metalloproteinases. The catalytic domain alone has proteolytic activity against other protein substrates and synthetic substrates.<ref name="X-ray">PMID:8137810</ref> | ||
==== Subsites ==== | ==== Subsites ==== | ||
Besides the catalytic site, the MMPs have other sites called subsites which can also interact with the substrates and inhibitors. Conventionally, the subsites on the left of the catalytic Zn2+ are designated as S1, S2, S3,..., Sn and the ones on the right are known as S1', S2', etc. | Besides the catalytic site, the MMPs have other sites called subsites which can also interact with the substrates and inhibitors. Conventionally, the subsites on the left of the catalytic Zn2+ are designated as S1, S2, S3, ..., Sn and the ones on the right are known as S1', S2', etc. | ||
One of these subsites, the S1' pocket, is the main subsite for the substrate recognition. This pocket is variable in amino acid composition and depth and can be used to classify the MMPs. | One of these subsites, the S1' pocket, is the main subsite for the substrate recognition. This pocket is variable in amino acid composition and depth and can be used to classify the MMPs. | ||
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=== Hinge domain === | === Hinge domain === | ||
It corresponds to a short linker region from G242 to P258, with the following sequence: GLSSNPIQPTGPSTPKP, between the catalytic and the hemopexin domains. The exact role of this domain isn't very well clear but it's known that autoproteolysis could occurred in | It corresponds to a short linker region from G242 to P258, with the following sequence: GLSSNPIQPTGPSTPKP, between the catalytic and the hemopexin domains. The exact role of this domain isn't very well clear but it's known that autoproteolysis could occurred in MMP-8 leading to an unstable protein and different mutants<ref name="hinge">PMID:9094424</ref> were made in the hinge region and shown that stability of MMP-8 could be increased, decreased or unchanged. Moreover, sequence alignements of collagenolytic MMPs in this hinge domain reveal that they all have the four prolines in the same positions, suggesting that these prolines could be important for the specific collagenolytic activity. | ||
=== Hemopexin domain === | === Hemopexin domain === | ||
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It seems that the collagen binds to two sites on MMP-8 : one in the catalytic site and another in the hemopexin domain. One hypothesis is that when the collagen binds to both sites, its helical structure is destabilized and unwound. Thus, the cleavage site of collagen is accessible and the cleavage reaction can occur.[http://www.jleukbio.org/content/81/4/870.full] | It seems that the collagen binds to two sites on MMP-8 : one in the catalytic site and another in the hemopexin domain. One hypothesis is that when the collagen binds to both sites, its helical structure is destabilized and unwound. Thus, the cleavage site of collagen is accessible and the cleavage reaction can occur.[http://www.jleukbio.org/content/81/4/870.full] | ||
Unfortunately, no structure of the full | Unfortunately, no structure of the full MMP-8 protein has been crystallized yet, but <scene name='71/719866/Human_prommp-1_structure/1'>here</scene> you can see in orange the hemopexin domain of human pro-MMP1 which is very well conserved between these two proteins, by the way you can find in this article: [http://www.fasebj.org/content/12/12/1075.full#ref-27 Matrix metalloproteinases: structures, evolution, and diversification,Irina Massova, Lakshmi P. Kotra, Rafael Fridman and Shahriar Mobashery], good pieces of information on conservations among the MMPs family. | ||
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The cleavage is at Gly775–Ile776 or Leu776 in each alpha-chain of the collagen molecule<ref name="hinge"/> and takes place at neutral pH. It 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 name="hinge"/> and takes place at neutral pH. It 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> | ||
There is no crystallized complex of | There is no crystallized complex of MMP-8 and the collagen, however you can see <scene name='71/719866/Mmp1_complexed_with_collagen/2'>here</scene> the complex of MMP-1 and a triple-helical collagen peptide, MMP-1 being very close to MMP-8 it gives an idea of the MMP8-collagen complex. | ||
