Matrix metalloproteinase: Difference between revisions

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Michal Harel, Alexander Berchansky

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-{{STRUCTURE_1su3|  PDB=1su3  | SIZE=300| SCENE= |right|   CAPTION= Human pro MMP1 complex with HEPES, sulfate, Ca+2, Cl-1, Na+1, Zn+2 ions, [[1su3]] }}
+<StructureSection load='M1.pdb' size='350' side='right' scene='MT1-MMP-TIMP-1_complex/Cv2/8' caption='Complex of MMP14 (magenta) and TIMP-1 (orange) with Ca+2 (green) and Zn+2 (grey) ions (PDB code [[3ma2]])'>
-'''Matrix metalloproteinases''' (MMP) are Zinc-dependent endopeptidases.  MMP degrades extracellular matrix proteins.  MMPs are produced by 28 different genes and are classified according to their protein substrates.  They are inhibited by proteases called tissue inhibitors of metalloproteinase (TIMP).  The pro-MMP contains a pro-peptide which must be removed to render the MMP active.  See [[MT1-MMP-TIMP-1 complex]] for details of the complex of MMP14 and the protein inhibitor TIMP-1.
+__TOC__
+== Function ==
+'''Matrix metalloproteinases''' (MMP) are Zinc-dependent endopeptidases.  MMP degrades extracellular matrix proteins.  They are inhibited by proteases called tissue inhibitors of metalloproteinase (TIMP).  The pro-MMP contains a pro-peptide which must be removed to render the MMP active<ref>PMID:10419448</ref>. See details in<br />
-{{TOC limit|limit=2}}
+* [[Matrix metalloproteinases]]<br />
+* [[Metalloproteases]]<br />
+* [[MT1-MMP-TIMP-1 complex]]<br />.
-==3D structures of matrix metalloproteinase==
+MMPs are produced by 28 different genes and are classified according to their protein substrates.<br />
+* '''MMP1''' cleaves collagens I, II, III, VII and X.<br />
+* '''MMP2''' cleaves collagen IV and denatured collagen.<br />
+* '''MMP3''' cleaves the core protein of aggrecan and plasminogen activator.<br />
+* '''MMP7''' cleaves proteoglycans, fibronectin, elastin and casein.<br />
+* '''MMP8''' cleaves aggrecan.<br />
+* '''MMP9''' cleaves gelatin.  See details in [[Molecular Playground/MMP9]]<br />
+* '''MMP10''' cleaves collagens III, IV, V, fibronectin,gelatin and aggrecan.<br />
+* '''MMP11''' cleaves peptides in human tumors.<br />
+* '''MMP12''' cleaves collagens I and III. See details in [[Matrix Metalloproteinase 12]] <br />
+* '''MMP13''' cleaves collagen II and laminin-5 γ2.<br />
+* '''MMP14''' is a membrane-type MMP which cleaves aggrecan.  See details in [[Molecular Playground/MMP14]]<br />
+* '''MMP16''' cleaves collagen III, proteoglycans, fibronectin, gelatin, vitronectin, laminin and α2-macroglobulin.<br />
+* '''MMP20''' cleaves E-cadherin.<br />
+* '''MMP23''' function is unknown.<br />
+* '''MMP adamalysin''' is a snake toxin.  See details in [[Atragin]]<br />
-===MMP1 interstitial collagenase===
+== Relevance ==
+MMPs have a role in cancer progression<ref>PMID:21087457</ref>.  MMP-2 and MMP-9 secretion is elevated in ovarian cancer and are associated with poor prognosis<ref>PMID:19360311</ref>.  MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases<ref>PMID:8315570</ref>.
-[[1su3]] – pro-hMMP – human
+{{Clear}}
-===MMP2 gelatinase-A===
+==MT1-MMP-TIMP-1 complex==
-[[1qib]] - hMMP catalytic domain (mutant) <BR />
+The human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (''e.g.'' <scene name='MT1-MMP-TIMP-1_complex/Cv2/9'>membrane type-1 matrix metalloproteinase (MT1-MMP)</scene> <font color='darkmagenta'><b>(darkmagenta)</b></font> and <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> <font color='magenta'><b>(magenta)</b></font>, <scene name='MT1-MMP-TIMP-1_complex/Cv2/10'>click to see structural comparison</scene>) that perform a wide variety of biological roles. In general, the MMPs are inhibited unselectively by all four known tissue inhibitors of metalloproteinases (TIMPs 1-4) which have 40-50% sequence identity. For example, <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> can form complex with <scene name='MT1-MMP-TIMP-1_complex/Cv/12'>wild-type TIMP-1</scene> ([[1uea]], <font color='orange'><b>colored orange</b></font>). <scene name='MT1-MMP-TIMP-1_complex/Cv/13'>The WT-TIMP-1 binding interface</scene> <font color='cyan'><b>(cyan)</b></font> is mainly composed of the N-terminal segment that approaches the active site, the AB loop (Thr33-Tyr35), the CD loop (Ala65-Cys70), and the EF loop (Thr97-Ser100). The pivotal residue, threonine 98 (Thr98), is shown as <font color='red'><b>red sticks</b></font>. In general, <scene name='MT1-MMP-TIMP-1_complex/Cv1/2'>five main chain hydrogen bonds</scene> (Cys1-Ser68, Val69-Met66, Gly71-Met66, Cys70-Glu67, and Cys70-Thr98) are intimately involved in the conformational stability of TIMP binding interface when bound to MMP.
-[[1rtg]] - hMMP hemopexin-like domain<BR />
+<scene name='MT1-MMP-TIMP-1_complex/Cv2/9'>Membrane type-1 matrix metalloproteinase (MT1-MMP)</scene> <font color='darkmagenta'><b>(darkmagenta)</b></font> also forms complex with <scene name='MT1-MMP-TIMP-1_complex/Cv2/11'>wild-type TIMP-1</scene> ([[2j0t]], <font color='orange'><b>colored orange</b></font>), producing <scene name='MT1-MMP-TIMP-1_complex/Cv2/12'>similar hydrogen bond network in the WT TIMP-1 binding interface</scene> as well as <scene name='MT1-MMP-TIMP-1_complex/Cv2/13'>in the case with MT3-MMP</scene>. This network of hydrogen bonds stabilizes the CD and EF loops that compose the binding interface. Importantly, the <scene name='MT1-MMP-TIMP-1_complex/Cv2/14'>hydrogen bond between Cys1 and Ser68 may position the amino and carboxyl groups of Cys1 to effectively coordinate the Zn2+ ion</scene>. However, this MT1-MMP-WT-TIMP-1 complex is not tight-binding. MT1-MMP is unique since even though it exhibits high structural homology to all MMPs, it is not inhibited by TIMP-1, <scene name='MT1-MMP-TIMP-1_complex/Cv3/1'>but is inhibited by the structural homologous TIMP-2</scene> ([[1bqq]]). <scene name='MT1-MMP-TIMP-1_complex/Cv2/15'>The single point mutation T98L</scene> (mutant TIMP-1 is colored in <span style="color:yellow;background-color:black;font-weight:bold;">yellow</span> with <font color='red'><b>T98L shown in red</b></font>) transformed TIMP-1 into a high affinity inhibitor of MT1-MMP ([[3ma2]]). WT-TIMP-1, WT-TIMP-2, and TIMP-1 T98L mutant have kinetic dissociation binding constant (K<sub>D</sub>) 1.53 x 10<sup>-6</sup>, 5.61 x 10<sup>-8</sup>, and 8.70 x 10<sup>-8</sup>, respectively. So, K<sub>D</sub> of WT-TIMP-2 is 2 orders of magnitude smaller than that of WT-TIMP-1, indicating the weak affinity between MT1-MMP and WT-TIMP-1. The TIMP-1 T98L mutant regained high-affinity binding to MT1-MMP, resulting in a 2 order of magnitude decrease in K<sub>D</sub>, similar to the case for WT-TIMP-2, the ''in vivo'' inhibitor of MT1-MMP. The overall structures of the complexes of <font color='darkmagenta'><b>MT1-MMP</b></font>-<font color='orange'><b>WT-TIMP-1</b></font> and <font color='violet'><b>MT1-MMP</b></font>-<span style="color:yellow;background-color:black;font-weight:bold;">mutant-T98L-TIMP-1</span> are <scene name='MT1-MMP-TIMP-1_complex/Cv2/17'>relatively similar</scene>. Even the structure of <font color='magenta'><b>MT3-MMP</b></font>-<font color='orange'><b>WT-TIMP-1</b></font> is <scene name='MT1-MMP-TIMP-1_complex/Cv2/18'>similar to those of MT1-MMP-TIMP-1s</scene> (with <font color='orange'><b>wild-type</b></font> and <span style="color:yellow;background-color:black;font-weight:bold;">TIMP-1 T98L mutant</span>). <scene name='MT1-MMP-TIMP-1_complex/Cv4/1'>Leu98 is pointing toward MT1-MMP residues Pro259 and Phe260, establishing a strong hydrophobic core</scene>, which is situated near the MT1-MMP <scene name='MT1-MMP-TIMP-1_complex/Cv4/3'>catalytic Zn2+ ion surrounded by His239, His243, and His249</scene>. So, this T98L replacement may stabilize the entire area by establishing a strong hydrophobic core upon binding to the enzyme. However, it seems unlikely that these additional bonds could
-[[1ks0]] – hMMP first fibronectin type II domain – NMR<BR />
+account for the entire binding effect between MT1-MMP and TIMP-1. Statistical analysis of the <scene name='MT1-MMP-TIMP-1_complex/Cv2/15'>key hydrogen bond</scene> stabilities in the TIMP-1 T98L mutant reveals that the hydrogen bonds network in mutant form is significantly more stable than that in WT-TIMP-1. Mutations that enhance hydrogen
-[[1cxw]] - hMMP second fibronectin type II domain – NMR<BR />
+bond stability contribute to the stability of the bound-like, less flexible, conformation of TIMP-1, which eventually results in increasing binding affinity for MT1-MMP. Thus, mutation affected the instrinsic dynamics of the inhibitor rather than its structure, thereby facilitating the interaction <ref name="Grossman">PMID:20545310</ref>.
-[[1j7m]] - hMMP third fibronectin type II domain (mutant) – NMR<BR />
-[[1eak]] – pro-hMMP catalytic domain (mutant) + peptide inhibitor<br />
-[[1hov]], [[1eub]] - hMMP catalytic domain + inhibitor– NMR<BR />
-[[1gxd]] – pro-hMMP (mutant) + TIMP-2
-===MMP3 stromelysin 1===
+==3D structures of matrix metalloproteinase==
+[[Matrix metalloproteinase 3D structures]]
-[[1qia]], [[1qic]], [[1cqr]], [[1slm]] - hMMP catalytic domain<BR />
-[[3ohl]], [[3oho]], [[1g49]], [[1ciz]], [[1b8y]], [[1caq]], [[1usn]], [[2usn]], [[1ums]], [[1umt]] – hMMP catalytic domain + inhibitor<br />
-[[1uea]] - hMMP catalytic domain + TIMP-1<BR />
-[[1oo9]] - hMMP catalytic domain + TIMP-1 N terminal<BR />
-[[2jt5]], [[2jt6]], [[2jnp]], [[3usn]], [[1sln]] - hMMP catalytic domain + inhibitor – NMR<BR />
-===MMP7 matrilysin===
-[[2y6c]], [[2y6d]] – hMMP residues 95-298 + inhibitor<br />
-===MMP8 neutrophil collagenase===
-[[3dng]], [[3dpe]], [[3dpf]], [[1zp5]], [[1jh1]], [[1jj9]], [[1i76]], [[1a85]], [[1mmb]] – hMMP catalytic domain + inhibitor<br />
-[[1i73]] - hMMP catalytic domain + peptide inhibitor<br />
-===MMP9 gelatinase-B===
-[[1l6j]] - pro-hMMP<BR />
-[[1gkc]] - hMMP catalytic domain + inhibitor<br />
-[[2ovx]], [[2ovz]], [[2ow0]], [[2ow1]], [[2ow2]], [[1gkd]] - hMMP catalytic domain (mutant) + inhibitor<br />
-===MMP10 stromelysin 2===
-[[1q3a]] - hMMP catalytic domain (mutant)
-===MMP11 stromelysin 3===
-[[1hv5]] - hMMP catalytic domain + inhibitor<br />
-===MMP12 macrophage===
-[[3ba0]], [[2oxu]] - hMMP<BR />
-[[2krj]], [[2k9c]] - hMMP catalytic domain – NMR<BR />
-[[1jk3]] - hMMP catalytic domain <BR />
-[[2poj]] - hMMP catalytic domain (mutant) - NMR<BR />
-[[2jxy]] - hMMP hemopexin-like domain - NMR<BR />
-[[3n2u]], [[3n2v]], [[2wo8]], [[2wo9]], [[2woa]], [[1utt]], [[1utz]], [[1ros]] – hMMP catalytic domain + inhibitor<br />
-[[3lk8]], [[3lik]], [[3lil]], [[3lir]], [[3ljg]], [[3nx7]], [[3lka]], [[3ehx]], [[3ehy]], [[3f15]], [[3f16]], [[3f17]], [[3f18]], [[3f19]], [[3f1a]], [[1y93]], [[1rmz]], [[1os2]], [[1os9]] - hMMP catalytic domain (mutant) + inhibitor<br />
-[[2k2g]], [[2z2d]] - hMMP catalytic domain + inhibitor - NMR<BR />
-[[2w0d]], [[1ycm]], [[1z3j]] - hMMP catalytic domain (mutant) + inhibitor - NMR<BR />
-===MMP13 collagenase 3===
-[[1cxv]] - MMP catalytic domain - mouse<BR />
-[[2yig]], [[3ljz]], [[3kec]], [[3kej]], [[3kek]], [[3kry]], [[3i7g]], [[3i7i]], [[3elm]], [[2pjt]], [[2ozr]], [[1xuc]], [[1xud]], [[1xur]], [[1you]] – hMMP catalytic domain + inhibitor<br />
-===MMP14 Membrane T1===
-[[3ma2]] – hMMP residues 112-292 + TIMP-1 (mutant) <BR />
-[[1buv]], [[1bqq]] - hMMP + TIMP-2<BR />
-[[3c7x]] – hMMP hemopexin-like domain
-===MMP16 Membrane T3===
-[[1rm8]] - hMMP catalytic domain + inhibitor<br />
-===MMP20 enamelysin===
-[[2jsd]] - hMMP catalytic domain + inhibitor - NMR<BR />
-===MMP23 CA-MMP===
-[[2k72]] – hMMP residues 254-290 - NMR<BR />
+</StructureSection>
+==References==
+<references/>
 [[Category:Topic Page]]