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Matrix Metalloproteinase-1 (MMP-1)

Matrix Metalloproteinase-1 (MMP-1)is interstitial collagenase and fibroblast collagenase. The enzyme in humans is encoded by the MMP1 gene. Human Fibroblast Collagenase (MMP-1) was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA.

Structure

The structure of MMP-1, just like the other members of matrix metalloproteinases family, is formed by different protein building blocks. The structure consists of a , a linker region and the Hemopexin-like Domain. The primary structure of MMP-1 was first published by Goldberg. Two main names for the primary structure are currently in use, the original one from which the first amino-acid starts with the signaling peptide and a second one where the first amino-acid starts counting from the prodomain (this is known as the proenzyme nomenclature).

Catalytic Domain

The Catalytic Domains of MMPs share very similar characteristics, having a general shape of oblate ellipsoid with a diameter of ~40Å. Despite the similarity of the Catalytic domains of MMPs, this entry will focus only on the structural features of MMP-1 Catalytic Domain.

Linker region

In MMPs the catalytic domain is followed by a stretch of 15–65 amino acid residues referred to as the linker or the hinge region. This region is rich in proline residues and replacement of those with alanine drastically reduced the collagenolytic activity of MMP-8 (neutrophil collagenase),19 indicating that the presence of the correct linker structure is important for collagenolysis.

Hemopexin-like domain

The hemopexin domain starts with Cys259 and forms a complete circle by joining to Cys447 in a disulphide bond that connects blade bI with blade bIV, giving this domain the characteristic four-bladed β-propeller structure. Each blade starts near the periphery with either the motif DAA or DAX, in which the Asp residues (Asp266, Asp359 and Asp408) coordinate the central calcium ion through their carbonyl oxygen atom. Glu310 provides the fourth coordination thus completing the acidic patch at the entrance of the central, solvent-accessible channel (Table 3). The side-chains of these residues form salt bridges to the neighbouring β-strands holding the entrance of the central channel together. Three water molecules are found trapped in the centre of this channel. These, however, are not involved in the coordination geometry of the calcium ion at the tunnel centre. Two of the water molecules are at positions corresponding to the sodium and chloride ion in the proMMP-1 structure.12 The water molecule corresponding to the sodium ion is at hydrogen-bonding distances to the carbonyl oxygen atom of Ile268, Ala312, Ala361 and Val410. The same cannot be said for the one corresponding to the chloride ion, which does not make any hydrogen bonds with the main-chain amides of the residues mentioned above. It is very likely that the presence of these ions is a consequence of the crystallisation conditions rather than a stability requirement for the hemopexin-like domain.

Overall Structural Characteristics

The of MMP-1 is composed of five highly twisted β-strands (sI-sV), three α-helix (hA-hC) and a total of eight loops, enclosing a total of five metal ions, three Ca2+ and two Zn2+, one of which with catalytic role. The Catalytic Domain (CAT) of MMP-1 starts with the F100 as the first amino-acid of the N-terminal loop of the CAT domain. This is different from the first published x-ray structure of the CAT domain was showed the truncated form of this domain, where the first 7 amino-acids are not present.

After the initial loop, the sequences follows to the first and longest β-sheet (sI). A second loop precedes large "amphipathic α-helix" (hA) that longitudinally spans protein site. The β-strands sII and sIII follows separated by the respective loops, loop 4 behing commonly designated as "short loop" briging sII to sIII. Following the sIII strand the sequence meets the 'S-shaped double loop' that is of primary importance for the peptide structure and catalytic activity (see further) as it extends to the cleft side "bulge", continuing to the only antiparallel β-strand sIV, which is prime importance for binding peptidic substrates or inhibitors by forming main chain Hydrogen bond. Following sIV, loop Gln186-Gly192 and β-strand sV are responsible for contributing with many ligands to the several metal ions present in the protein. A large open loop follows sV which has proven importance in substrate specificity within the MMPs family. A specific region (183)RWTNNFREY(191) as been identified as a critical segment of matrix metalloproteinase 1 for the expression of collagenolytic activity. On C-terminal part of the CAT Domain the hB α-helix, known as the "active-site helix" encompasses part of the "zinc-binding consensus sequence" HEXXHXXGXXH that is characteristic of the Metzincin superfamily. The α-helix hB finishes abruptly at Gly225 where the last loop of the domain starts. This last loop contains the "specificity loop" which is the shortest in the MMPs family. The Catalytic Domain ends at Gly261 with α-helix hC.

Function

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. MMP-1, as with most MMP's, is secreted as inactive proproteins which is later activated when cleaved by extracellular proteases.

Medical Implications

Research has shown that MMP-1 may have many health implications. MMP-1 plays an important role in diverse physiologic processes such as development, tissue morphogenesis, and wound repair. MMP-1 plays an important role in the remodeling of collagenous extracellular matrix in various physiologic and pathologic situations. The enzyme is expressed by a wide variety of cell types, including over 30 cell types. MMP-1 gene expression has been shown to be a prognostic factor for local recurrence and metastasis in human chondrosarcoma. MMP-1 gene expression analysis of atypical ductal hyperplastic tissues from patients with and without a history of breast cancer, identifying MMP-1 as a candidate marker that may be useful for identification of breast lesions that can develop into cancer.