MASP1 (protein) explained

Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by the MASP1 gene.^{[1] [2] [3]}

MASP-1 is involved in the lectin pathway of the complement system and is responsible for activating MASP-2 and MASP-3.^[4] It is also involved in the process of cleaving complement proteins, C4 and C2, into fragments to form a C3-convertase.^[5]

Function

MASP-1 is a serine protease that functions as a component of the lectin pathway of complement activation. The complement pathway plays an essential role in the innate and adaptive immune response as it allows the body to clear foreign material.^[6] MASP-1 is synthesized as a zymogen and is activated when it creates a complex of proteins with the pathogen recognition molecules oft the lectin pathway: the mannose-binding lectin and the ficolins. This protein is directly involved in complement activation because MASP-1 activates MASP-2 by cleaving (cutting off a piece) a MASP-2 zymogen.^[7] MASP-2 is then able to cleave C4 into proteins C4a and C4b. MASP-1 is also responsible for creating C3 convertase by cleaving C2 into C2b and C2a. C2a and C4b are used to create C3 convertase, a complex that will then be able to cleave C3 into C3a and C3b. However, MASP-1 is useful for biological pathways other than the complement pathway, such as blood clots. MASP-1 can cleave coagulation pathway proteins such as PAR-4, fibrinogen, and factor XIII which leads to high clot and fibrin generation.^[8] A spliced variant of this gene, which lacks the serine protease domain, functions as an inhibitor of the complement pathway.^[3]

Structure

MASP-1’s structure is similar to other MASP proteins. The MASP1 gene encodes MASP-1 as well as MASP-3 (via alternative splicing).^[9] Despite being made from different genes and spliced genes, all MASP proteins have the same structure of a heavy/alpha chain, a light/beta chain, and an interconnecting cysteine disulfide bond. The heavy chain is made up of two CUB domains and two complement control protein (CCP) domains that are connected by an epidermal growth factor segment (EGF). However, the full crystal structure of MASP proteins has not yet been formulated.^[10]

Clinical significance

MASP1 gene changes can lead to several diseases in patients due to subsequent MASP-1 protein changes. MASP1 gene changes (polymorphisms) can lead to systemic inflammatory response syndrome (SIRS)/sepsis, malpuech facial clefting (3MC) syndrome, and bacterial colonization in those with cystic fibrosis. Also, MASP-1 is essential for stem cell transplantation as it is involved in the transportation of bone marrow stem cells to the blood.^[11] Furthermore, single-nucleotide polymorphisms (SNPs) in MASP1 genes can lead to impaired blood clotting and complement activation.^[12] Overproduction of MASP-1 proteins can also be related to some diseases. For example, cardiovascular diseases increase MASP-1 levels, especially in cases such as subacute myocardial infarction. MASP-1 is also upregulated in patients with uterine leiomyosarcoma, and it can potentially activate the alternative pathway of complement in inflammatory arthritis patients. Hepatitis C (HCV), a liver disease, is associated with MASP-1 due to the localization of high concentrations of MASP-1 in infected livers. Higher levels of MASP-1 correlated with severe HCV-related liver fibrosis.

See also

• Complement system
• Mannan-binding lectin
• MASP2 (protein)

Further reading

• Guey LT, García-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M, Rothman N, Vellalta G, Calle ML, Marenne G, Tardón A, Carrato A, García-Closas R, Serra C, Silverman DT, Chanock S, Real FX, Malats N . 6 . Genetic susceptibility to distinct bladder cancer subphenotypes . European Urology . 57 . 2 . 283–292 . February 2010 . 19692168 . 3220186 . 10.1016/j.eururo.2009.08.001 .
• Petersen SV, Thiel S, Jensenius JC . The mannan-binding lectin pathway of complement activation: biology and disease association . Molecular Immunology . 38 . 2–3 . 133–149 . August 2001 . 11532276 . 10.1016/S0161-5890(01)00038-4 .
• Rajaraman P, Brenner AV, Butler MA, Wang SS, Pfeiffer RM, Ruder AM, Linet MS, Yeager M, Wang Z, Orr N, Fine HA, Kwon D, Thomas G, Rothman N, Inskip PD, Chanock SJ . 6 . Common variation in genes related to innate immunity and risk of adult glioma . Cancer Epidemiology, Biomarkers & Prevention . 18 . 5 . 1651–1658 . May 2009 . 19423540 . 2771723 . 10.1158/1055-9965.EPI-08-1041 .
• Dobó J, Harmat V, Beinrohr L, Sebestyén E, Závodszky P, Gál P . MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity . Journal of Immunology . 183 . 2 . 1207–1214 . July 2009 . 19564340 . 10.4049/jimmunol.0901141 . free .
• Skjoedt MO, Hummelshoj T, Palarasah Y, Honore C, Koch C, Skjodt K, Garred P . A novel mannose-binding lectin/ficolin-associated protein is highly expressed in heart and skeletal muscle tissues and inhibits complement activation . The Journal of Biological Chemistry . 285 . 11 . 8234–8243 . March 2010 . 20053996 . 2832975 . 10.1074/jbc.M109.065805 . free .
• Han S, Lan Q, Park AK, Lee KM, Park SK, Ahn HS, Shin HY, Kang HJ, Koo HH, Seo JJ, Choi JE, Ahn YO, Chanock SJ, Kim H, Rothman N, Kang D . 6 . Polymorphisms in innate immunity genes and risk of childhood leukemia . Human Immunology . 71 . 7 . 727–730 . July 2010 . 20438785 . 2967770 . 10.1016/j.humimm.2010.04.004 .
• Kocsis A, Kékesi KA, Szász R, Végh BM, Balczer J, Dobó J, Závodszky P, Gál P, Pál G . 6 . Selective inhibition of the lectin pathway of complement with phage display selected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: significant contribution of MASP-1 to lectin pathway activation . Journal of Immunology . 185 . 7 . 4169–4178 . October 2010 . 20817870 . 10.4049/jimmunol.1001819 . free . 10831/91219 . free .
• Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL . 6 . Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome . Nature Genetics . 43 . 3 . 197–203 . March 2011 . 21258343 . 3045628 . 10.1038/ng.757 .
• Megyeri M, Makó V, Beinrohr L, Doleschall Z, Prohászka Z, Cervenak L, Závodszky P, Gál P . 6 . Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function . Journal of Immunology . 183 . 5 . 3409–3416 . September 2009 . 19667088 . 10.4049/jimmunol.0900879 . free .
• Sirmaci A, Walsh T, Akay H, Spiliopoulos M, Sakalar YB, Hasanefendioğlu-Bayrak A, Duman D, Farooq A, King MC, Tekin M . 6 . MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes . American Journal of Human Genetics . 87 . 5 . 679–686 . November 2010 . 21035106 . 2978960 . 10.1016/j.ajhg.2010.09.018 .
• Hosgood HD, Menashe I, He X, Chanock S, Lan Q . PTEN identified as important risk factor of chronic obstructive pulmonary disease . Respiratory Medicine . 103 . 12 . 1866–1870 . December 2009 . 19625176 . 2783799 . 10.1016/j.rmed.2009.06.016 .
• Hosgood HD, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, He X, Chatterjee N, Caporaso NE, Zhu Y, Chanock SJ, Zheng T, Lan Q . 6 . Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway . Carcinogenesis . 29 . 10 . 1938–1943 . October 2008 . 18676680 . 2722857 . 10.1093/carcin/bgn178 .
• Kang JU, Koo SH, Kwon KC, Park JW, Kim JM . Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung . BMC Cancer . 9 . 237 . July 2009 . 19607727 . 2716371 . 10.1186/1471-2407-9-237 . free .
• Skjoedt MO, Palarasah Y, Munthe-Fog L, Jie Ma Y, Weiss G, Skjodt K, Koch C, Garred P . 6 . MBL-associated serine protease-3 circulates in high serum concentrations predominantly in complex with Ficolin-3 and regulates Ficolin-3 mediated complement activation . Immunobiology . 215 . 11 . 921–931 . November 2010 . 19939495 . 10.1016/j.imbio.2009.10.006 .
• Degn SE, Hansen AG, Steffensen R, Jacobsen C, Jensenius JC, Thiel S . MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation . Journal of Immunology . 183 . 11 . 7371–7378 . December 2009 . 19917686 . 10.4049/jimmunol.0902388 . free .
• Rajaraman P, Brenner AV, Neta G, Pfeiffer R, Wang SS, Yeager M, Thomas G, Fine HA, Linet MS, Rothman N, Chanock SJ, Inskip PD . 6 . Risk of meningioma and common variation in genes related to innate immunity . Cancer Epidemiology, Biomarkers & Prevention . 19 . 5 . 1356–1361 . May 2010 . 20406964 . 3169167 . 10.1158/1055-9965.EPI-09-1151 .
• Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A . 6 . Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study . Lancet . 372 . 9652 . 1828–1834 . November 2008 . 18842294 . 5983350 . 10.1016/S0140-6736(08)61348-3 .
• Shen M, Vermeulen R, Rajaraman P, Menashe I, He X, Chapman RS, Yeager M, Thomas G, Burdett L, Hutchinson A, Yuenger J, Chanock S, Lan Q . 6 . Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei, China . Environmental and Molecular Mutagenesis . 50 . 4 . 285–290 . May 2009 . 19170196 . 2666781 . 10.1002/em.20452 . 2009EnvMM..50..285S .
• Duus K, Thielens NM, Lacroix M, Tacnet P, Frachet P, Holmskov U, Houen G . CD91 interacts with mannan-binding lectin (MBL) through the MBL-associated serine protease-binding site . The FEBS Journal . 277 . 23 . 4956–4964 . December 2010 . 21054788 . 10.1111/j.1742-4658.2010.07901.x . 31526986 . free .
• Degn SE, Jensen L, Gál P, Dobó J, Holmvad SH, Jensenius JC, Thiel S . Biological variations of MASP-3 and MAp44, two splice products of the MASP1 gene involved in regulation of the complement system . Journal of Immunological Methods . 361 . 1–2 . 37–50 . September 2010 . 20673767 . 10.1016/j.jim.2010.07.006 .

Notes and References

1. Takada F, Takayama Y, Hatsuse H, Kawakami M . A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum . Biochemical and Biophysical Research Communications . 196 . 2 . 1003–1009 . October 1993 . 8240317 . 10.1006/bbrc.1993.2349 .
2. Sato T, Endo Y, Matsushita M, Fujita T . Molecular characterization of a novel serine protease involved in activation of the complement system by mannose-binding protein . International Immunology . 6 . 4 . 665–669 . April 1994 . 8018603 . 10.1093/intimm/6.4.665 .
3. Web site: Entrez Gene: mannan-binding lectin serine peptidase 1 (C4/C2 activating component of Ra-reactive factor).
4. Book: Sekine H, Takahashi M, Iwaki D, Fujita T . Complement Therapeutics . The Role of MASP-1/3 in Complement Activation . 735 . 41–53 . 2013 . 23402018 . 10.1007/978-1-4614-4118-2_3 . 978-1-4614-4118-2 . Advances in Experimental Medicine and Biology . Lambris JD, Holers VM, Ricklin D . Springer US . New York, NY .
5. Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T . Proteolytic activities of two types of mannose-binding lectin-associated serine protease . Journal of Immunology . 165 . 5 . 2637–2642 . September 2000 . 10946292 . 10.4049/jimmunol.165.5.2637 . free .
6. Book: Atik T, Koparir A, Bademci G, Foster J, Altunoglu U, Mutlu GY, Bowdin S, Elcioglu N, Tayfun GA, Atik SS, Ozen M, Ozkinay F, Alanay Y, Kayserili H, Thiel S, Tekin M . Serine Proteases in the Lectin Pathway of the Complement System . 6 . Proteases in Physiology and Pathology . Orphanet Journal of Rare Diseases . 10 . 397–420 . September 2015 . 7120406 . 10.1007/978-981-10-2513-6_18 . 26419238 . 978-981-10-2512-9 .
7. Dobó J, Schroeder V, Jenny L, Cervenak L, Závodszky P, Gál P . Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation . Molecular Immunology . 61 . 2 . 69–78 . October 2014 . 24935208 . 10.1016/j.molimm.2014.05.013 . XXV International Complement Workshop September 14-18, 2014 - Rio de Janeiro, Brazil .
8. Kjaer TR, Thiel S, Andersen GR . Toward a structure-based comprehension of the lectin pathway of complement . Molecular Immunology . 56 . 4 . 413–422 . December 2013 . 23911397 . 10.1016/j.molimm.2013.05.007 .
9. Book: Takahashi M, Mori S, Shigeta S, Fujita T . Current Topics in Innate Immunity . Role of MBL-associated Serine Protease (MASP) on Activation of the Lectin Complement Pathway . 598 . 93–104 . 2007 . 17892207 . 10.1007/978-0-387-71767-8_8 . Springer . 978-0-387-71767-8 . Advances in Experimental Medicine and Biology . Lambris JD .
10. Garred P, Genster N, Pilely K, Bayarri-Olmos R, Rosbjerg A, Ma YJ, Skjoedt MO . A journey through the lectin pathway of complement-MBL and beyond . Immunological Reviews . 274 . 1 . 74–97 . November 2016 . 27782323 . 10.1111/imr.12468 . 37084404 .
11. Cedzyński M, Świerzko AS . Components of the Lectin Pathway of Complement in Haematologic Malignancies . Cancers . 12 . 7 . 1792 . July 2020 . 32635486 . 7408476 . 10.3390/cancers12071792 . free .
12. Beltrame MH, Boldt AB, Catarino SJ, Mendes HC, Boschmann SE, Goeldner I, Messias-Reason I . MBL-associated serine proteases (MASPs) and infectious diseases . Molecular Immunology . 67 . 1 . 85–100 . September 2015 . 25862418 . 7112674 . 10.1016/j.molimm.2015.03.245 . 15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden .