Biology:Matrix metallopeptidase 13

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene.[1][2] It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form.[3] MMP-13 has a predicted molecular weight around 54 kDa.[4] It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain PDB: 1PEX​. Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.[5]

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. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The protein encoded by this gene cleaves type II collagen more efficiently than types I and III[citation needed]. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.[2]

Regulation

Transcriptional regulation of MMP-13 is tightly controlled due to its potent proteolytic capacity. There are several binding domains for various transcription factors including AP-1, PEA-3 and OSE-2 as well as a sequence with homology to a TGF-β inhibitory element (TIE). Moreover, several cytokines and growth factors have been demonstrated to affect Mmp13 gene expression, including parathyroid hormone, IGF-1, TGF-β, hepatocyte growth factor and many inflammatory cytokines such as IL-1α and IL-1β.[6]

The upstream regulatory region of the Mmp13 gene contains a number of transcription factor binding sites but it was recently discovered that there is a conserved forkhead response element (FHRE) consensus sequence for FOXO3a in the human, mouse and rat Mmp13 promoter. Endogenous FOXO3a activation results in marked upregulation of Mmp13 expression which is capable of promoting extracellular matrix degradation and apoptotic cell death. [7]

Clinical Relevance

MMP-13 has long been a protein of interest in the context of osteoarthritis and rheumatoid arthritis.[8]

The role of MMP-13 has also been thoroughly examined in atherosclerosis, specifically in potentially reducing the collagen content of the fibrous cap. [9] [10] [11] [12] [13]

References

  1. ↑ "Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas". The Journal of Biological Chemistry 269 (24): 16766–73. June 1994. doi:10.1016/S0021-9258(19)89457-7. PMID 8207000. 
  2. ↑ 2.0 2.1 "Entrez Gene: MMP13 matrix metallopeptidase 13 (collagenase 3)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4322. 
  3. ↑ "Biochemical and Biological Attributes of Matrix Metalloproteinases". Progress in Molecular Biology and Translational Science 147: 1–73. 2017. doi:10.1016/bs.pmbts.2017.02.005. ISBN 9780128116371. PMID 28413025. 
  4. ↑ "MMP13 (human)". https://www.phosphosite.org/proteinAction.action?id=14470&showAllSites=true. 
  5. ↑ "Matrix metalloproteinases in tumor invasion". Cellular and Molecular Life Sciences 57 (1): 5–15. January 2000. doi:10.1007/s000180050495. PMID 10949577. 
  6. ↑ "The structure, regulation, and function of human matrix metalloproteinase-13". Critical Reviews in Biochemistry and Molecular Biology 37 (3): 149–66. 2003. doi:10.1080/10409230290771483. PMID 12139441. 
  7. ↑ "FOXO3a (Forkhead Transcription Factor O Subfamily Member 3a) Links Vascular Smooth Muscle Cell Apoptosis, Matrix Breakdown, Atherosclerosis, and Vascular Remodeling Through a Novel Pathway Involving MMP13 (Matrix Metalloproteinase 13)". Arteriosclerosis, Thrombosis, and Vascular Biology 38 (3): 555–565. March 2018. doi:10.1161/ATVBAHA.117.310502. PMID 29326312. 
  8. ↑ "Joint diseases and matrix metalloproteinases: a role for MMP-13". Current Pharmaceutical Biotechnology 9 (1): 47–54. February 2008. doi:10.2174/138920108783497659. PMID 18289056. 
  9. ↑ "Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques". Circulation 99 (19): 2503–9. May 1999. doi:10.1161/01.cir.99.19.2503. PMID 10330380. 
  10. ↑ "MMP-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques.". Circulation 112 (17): 2708–2715. October 2005. doi:10.1161/CIRCULATIONAHA.105.562041. PMID 16230484. 
  11. ↑ "Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype". Atherosclerosis 204 (1): 26–33. May 2009. doi:10.1016/j.atherosclerosis.2009.01.025. PMID 19233360. 
  12. ↑ "Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology 31 (11): 2464–72. November 2011. doi:10.1161/ATVBAHA.111.231563. PMID 21903941. 
  13. ↑ "Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata". Arteriosclerosis, Thrombosis, and Vascular Biology 34 (6): 1179–86. June 2014. doi:10.1161/ATVBAHA.114.303326. PMID 24723558. 

Further reading

External links

  • The MEROPS online database for peptidases and their inhibitors: M10.013



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