MMP-27 was discovered and cloned in 1998 by Yang and Kurkinen.[2] Initially compared to the so-called Chicken MMP (CMMP), MMP-27 actually shows very little sequence homology with this protease. Sequence homology predicts that the human MMP-27 gene encodes the canonical domains shared by most MMPs (annotation based on Uniprot entry Q9H306): (i) a signal peptide (residues 1-17), (ii) a propeptide (18-98) containing the cysteine switch motif (89-96), (iii) a catalytic domain (99-263) containing the typical HEXXHXXGXXH motif of the metzincins (M10 and M12 families of the MEROPS[2] database), (iv) a proline-rich hinge region (264-278) and (v) a hemopexin-like domain (279-465) folded as a four-bladed β-propeller through disulfide bond formation between the two flanking Cys residues (Cys279 and Cys465). MMP-27 could be classified in the stromelysin group of MMPs, since MMP-27 shows 51,6% homology with stromelysin-2 (MMP-10) and localizes in the cluster of MMPs located on chromosome 11.
Like the six known MT-MMPs, human MMP-27 is prolonged by an additional C-terminal domain (466-513). The Spoctopus algorithm for topological prediction[3] suggests that this C-terminal extension (CTE) includes a potential transmembrane domain (490-510). However, this sequence is less hydrophobic than in transmembrane MT-MMPs (MMP-14, -15, -16 and -24) as it contains hydrophilic/charged residues, in particular His492, Lys493, His504 and Lys507.
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. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases.[4]
Cominelli A. and colleagues demonstrated that MMP-27 is an unusual protease which is not secreted and is efficiently retained in the endoplasmic reticulum in three mammalian cell lines.[5] Deletion mutants and swapping with recombinant MMP-10 demonstrate that the unique MMP-27 C-terminal extension (CTE) is necessary and sufficient for endoplasmic reticulum retention but does not provide a stable membrane anchorage. Despite sequence homology with MT-MMPs, the CTE is not a transmembrane domain and does not interact permanently with membrane. This unique feature for an MMP raises important questions about potential functions of MMP-27, which remains to be investigated.
Clinical significance
Sparse information about MMP-27 expression was found in studies of gene expression profiling (micro-array) or in expression pattern analysis of MMP family members during developmental, physiological or pathological processes. MMP-27 transcript is detected in almost every tissue, except the brain, with the highest expression found in the liver during mouse development[6] In the adult, MMP-27 mRNA is mostly abundant in anti-IgG/IgM stimulated B lymphocytes,[7] bone and kidney but is present at lower levels in the heart.[8]
A recent investigation of the transcriptome from distinct tissue compartments of the menstrual endometrium disclosed specific MMP-27 overexpression in areas of stromal breakdown.[9] In another transcriptomic study, MMP-27 was found to be increased in the human endometrium at the end of the secretory phase, before menstruation.[10] Moreover, MMP-27 expression is down-regulated in macrophages when co-cultured with ovarian cancer cells[11] but up-regulated in cartilages from patients with osteoarthritis[12] or in abdominal aortic aneurysms.[13] MMP-27 was also identified, at the protein level, in MDA-MB-231 breast cancer cell line[14] and in primary human breast cancer.[15] Recently, MMP-27 has been demonstrated to be expressed by CD163+/CD206+ macrophages in the human endometrium and in superficial endometriotic lesions.[16]
↑Yang M, Kurkinen M (1998). "Cloning and characterization of a novel matrix metalloproteinase (MMP), CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain". J. Biol. Chem. 273 (28): 17893–900. doi:10.1074/jbc.273.28.17893. PMID9651395.
↑Viklund H, Bernsel A, Skwark M, Elofsson A (2008). "SPOCTOPUS: a combined predictor of signal peptides and membrane protein topology". Bioinformatics. 24 (24): 2928–9. doi:10.1093/bioinformatics/btn550. PMID18945683.
↑Cominelli A, Halbout M, N'Kuli F, Lemoine P, Courtoy PJ, Marbaix E, Tyteca D, Henriet P (2014). "A unique C-terminal domain allows retention of matrix metalloproteinase-27 in the endoplasmic reticulum". Traffic. 15 (4): 401–17. doi:10.1111/tra.12149. PMID24548619.
↑Nuttall RK, Sampieri CL, Pennington CJ, Gill SE, Schultz GA, Edwards DR (2004). "Expression analysis of the entire MMP and TIMP gene families during mouse tissue development". FEBS Lett. 563 (1–3): 129–34. doi:10.1016/S0014-5793(04)00281-9. PMID15063736.
↑Bar-Or A, Nuttall RK, Duddy M, Alter A, Kim HJ, Ifergan I, Pennington CJ, Bourgoin P, Edwards DR, Yong VW (2003). "Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis". Brain. 126 (Pt 12): 2738–49. doi:10.1093/brain/awg285. PMID14506071.
↑Bernal F, Hartung HP, Kieseier BC (2005). "Tissue mRNA expression in rat of newly described matrix metalloproteinases". Biol. Res. 38 (2–3): 267–71. doi:10.4067/S0716-97602005000200016. PMID16238105.
↑Gaide Chevronnay HP, Galant C, Lemoine P, Courtoy PJ, Marbaix E, Henriet P (2009). "Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium". Endocrinology. 150 (11): 5094–105. doi:10.1210/en.2009-0750. PMID19819954.
↑Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, Le Shay N, Nezhat CN, Kempson R, Lessey BA, Nayak NR, Giudice LC (2006). "Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women". Endocrinology. 147 (3): 1097–121. doi:10.1210/en.2005-1076. PMID16306079.
↑Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Plüddemann A, Charles K, Gordon S, Balkwill FR (2006). "Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype". J. Immunol. 176 (8): 5023–32. doi:10.4049/jimmunol.176.8.5023. PMID16585599.
↑Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM (2004). "Expression profiling of metalloproteinases and their inhibitors in cartilage". Arthritis Rheum. 50 (1): 131–41. doi:10.1002/art.11433. PMID14730609.
↑Lamblin N, Ratajczak P, Hot D, Dubois E, Chwastyniak M, Beseme O, Drobecq H, Lemoine Y, Koussa M, Amouyel P, Pinet F (2010). "Profile of macrophages in human abdominal aortic aneurysms: a transcriptomic, proteomic, and antibody protein array study". J. Proteome Res. 9 (7): 3720–9. doi:10.1021/pr100250s. PMID20513153.
↑Hegedüs L, Cho H, Xie X, Eliceiri GL (2008). "Additional MDA-MB-231 breast cancer cell matrix metalloproteinases promote invasiveness". J. Cell. Physiol. 216 (2): 480–5. doi:10.1002/jcp.21417. PMID18286480.
↑Cominelli A, Gaide Chevronnay HP, Lemoine P, Courtoy PJ, Marbaix E, Henriet P (2014). "Matrix metalloproteinase-27 is expressed in CD163+/CD206+ M2 macrophages in the cycling human endometrium and in superficial endometriotic lesions". Mol. Hum. Reprod. 20 (8): 767–75. doi:10.1093/molehr/gau034. PMID24810263.
External links
The MEROPS online database for peptidases and their inhibitors: M10.027