Serpiny: Różnice pomiędzy wersjami

Aktywność inhibitora proteaz w [[osocze krwi|osoczu krwi]] po raz pierwszy odnotowano pod koniec pierwszej dekady XIX wieku<ref>{{cytuj pismo | nazwisko = Fermi imię = C | nazwisko2 = Personsi | imię2 = L | name-list-format = vanc | tytuł = Untersuchungen uber die enzyme, Vergleichende Studie | trans-title = Studies on the enzyme, Comparative study | languagejęzyk = German | czasopismo = Z Hyg Infektionskr | data = 1984 | wydanie = 18 | strony = 83–89}}</ref>, ale izolacja serpin doszła do skutku dopiero w latach pięćdziesiątych XX wieku – były to [[antytrombina]] i [[alfa1-antytrypsyna]]<ref>{{cytuj pismo | nazwisko = Schultz imię = H | nazwisko2 = Guilder | imię2 = I | nazwisko3 = Heide | imię3 =K | nazwisko4 = Schoenenberger | imię4 = M | nazwisko5 = Schwick | imię5 = G | name-list-format = vanc | tytuł = Zur Kenntnis der alpha-globulin des menschlichen normal serums | trans-title = For knowledge of the alpha - globulin of human normal serums | languagejęzyk = de | czasopismo = Naturforsch | data = 1955 | wydanie = 10 | strony = 463}}</ref>. Początkowe badania skupiały się na ich roli w chorobach [[człowiek rozumny|człowieka]]. [[Niedobór alfa1-antytrypsyny]] należy do naczęstszych chorób genetycznych, powoduje [[rozedma płuc|rozedmę płuc]]<ref name="Janciauskiene_2011"/><ref name="Laurell_2013">{{cytuj pismo | vauthors = Laurell CB, Eriksson S | tytuł = The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963 | czasopismo = Copd | wolumin = 10 Suppl 1 | wydanie = | strony = 3–8 | rok = 2013 | pmid = 23527532 | doi = 10.3109/15412555.2013.771956}}</ref><ref name="de_Serres_2002">{{cytuj pismo | nazwisko = de Serres | imię = Frederick J.| tytuł = Worldwide Racial and Ethnic Distribution of α-Antitrypsin Deficiency | czasopismo = CHEST Journal | data = 1 November 2002 | wolumin = 122 | wydanie = 5 | strony = 1818 | doi = 10.1378/chest.122.5.1818}}</ref>. Niedobór antytrombiny powoduje [[zakrzepica|zakrzepicę]]<ref>{{cytuj pismo | vauthors = Egeberg O | tytuł = Inherited antithrombin deficiency causing thrombophilia | czasopismo = Thrombosis Et Diathesis Haemorrhagica | wolumin = 13 | strony = 516–30 | data = June 1965 | pmid = 14347873}}</ref><ref>{{cytuj pismo | autor = Patnaik MM, Moll S | tytuł = Inherited antithrombin deficiency: a review | czasopismo = Haemophilia | wolumin = 14 | wydanie = 6 | strony = 1229–39 | data = 2008 | pmid = 19141163 | doi = 10.1111/j.1365-2516.2008.01830.x}}</ref>.

Many [[mammal]]ian serpins have been identified that share no obvious orthology with a human serpin counterpart. Examples include numerous [[rodent]] serpins (particularly some of the [[murine]] intracellular serpins) as well as the [[uterine serpin]]s. The term uterine serpin refers to members of the serpin A clade that are encoded by the SERPINA14 gene. Uterine serpins are produced by the [[endometrium]] of a restricted group of mammals in the [[Laurasiatheria]] clade under the influence of [[progesterone]] or [[estrogen]]<ref name="Padua_2010">{{citecytuj journalpismo | vauthors = Padua MB, Kowalski AA, Cañas MY, Hansen PJ | titletytuł = The molecular phylogeny of uterine serpins and its relationship to evolution of placentation | journalczasopismo = FASEB Journal | volumewolumin = 24 | issuewydanie = 2 | strony = 526–37 | datedata = February 2010 | pmid = 19825977 | doi = 10.1096/fj.09-138453}}</ref>. They are probably not functional proteinase inhibitors and may function during pregnancy to inhibit maternal immune responses against the [[conceptus]] or to participate in transplacental transport<ref name="Padua_Hansen_2010">{{citecytuj journalpismo | vauthors = Padua MB, Hansen PJ | titletytuł = Evolution and function of the uterine serpins (SERPINA14) | journalczasopismo = American Journal of Reproductive Immunology | volumewolumin = 64 | issuewydanie = 4 | stronys = 265–74 | datedata = October 2010 | pmid = 20678169 | doi = 10.1111/j.1600-0897.2010.00901.x}}</ref>.

The ''[[Drosophila melanogaster]]'' genome contains 29&nbsp;serpin encoding genes. Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and three in serpin clade K with the remaining twelve classified as orphan serpins not belonging to any clade<ref name="Reichhart_2005" >{{citecytuj journalpismo | vauthors = Reichhart JM | titletytuł = Tip of another iceberg: Drosophila serpins | journalczasopismo = Trends in Cell Biology | volumewolumin = 15 | issuewydanie = 12 | strony = 659–65 | datedata = December 2005 | pmid = 16260136 | doi = 10.1016/j.tcb.2005.10.001}}</ref>. The clade classification system is difficult to use for ''Drosophila'' serpins and instead a nomenclature system has been adopted that is based on the position of serpin genes on the ''Drosophila'' [[chromosome]]s. Thirteen of the ''Drosophila'' serpins occur as isolated genes in the genome (including Serpin-27A, see below), with the remaining 16 organised into three gene clusters that occur at chromosome positions 28D (2&nbsp;serpins), 42D (5&nbsp;serpins), 43A (4&nbsp;serpins), 77B (3&nbsp;serpins) and 88E (2&nbsp;serpins)<ref name="Reichhart_2005"/><ref name="Tang_2008">{{citecytuj journalpismo | vauthors = Tang H, Kambris Z, Lemaitre B, Hashimoto C | titletytuł = A serpin that regulates immune melanization in the respiratory system of Drosophila | journalczasopismo = Developmental Cell | volumewolumin = 15 | issuewydanie = 4 | stronys = 617–26 | datedata = October 2008 | pmid = 18854145 | pmc = 2671232 | doi = 10.1016/j.devcel.2008.08.017}}</ref><ref name="Scherfer_2008">{{citecytuj journalpismo | vauthors = Scherfer C, Tang H, Kambris Z, Lhocine N, Hashimoto C, Lemaitre B | titletytuł = Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation | journalczasopismo = Developmental Biology | volumewolumin = 323 | issuewydanie = 2 | strony = 189–96 | datedata = November 2008 | pmid = 18801354 | doi = 10.1016/j.ydbio.2008.08.030}}</ref>.

Studies on ''Drosophila'' serpins reveal that Serpin-27A inhibits the Easter protease (the final protease in the Nudel, Gastrulation Defective, Snake and Easter proteolytic cascade) and thus controls [[Regional specification#Dorsal/ventral axis|dorsoventral patterning]]. Easter functions to cleave Spätzle (a chemokine-type ligand), which results in [[Toll-like receptor|toll-mediated]] signaling. As well as its central role in embryonic patterning, toll signaling is also important for the [[Innate immune system#Host defense in invertebrates|innate immune response]] in insects. Accordingly, serpin-27A also functions to control the insect immune response<ref>{{citecytuj journalpismo | vauthors = Rushlow C | titletytuł = Dorsoventral patterning: a serpin pinned down at last | journalczasopismo = Current Biology | volumewolumin = 14 | issuewydanie = 1 | stronys = R16-8 | datedata = January 2004 | pmid = 14711428 | doi = 10.1016/j.cub.2003.12.015}}</ref><ref>{{citecytuj journalpismo | vauthors = Ligoxygakis P, Roth S, Reichhart JM | titletytuł = A serpin regulates dorsal-ventral axis formation in the Drosophila embryo | journalczasopismo = Current Biology | volumewolumin = 13 | issuewydanie = 23 | strony = 2097–102 | datedata = December 2003 | pmid = 14654000 | doi = 10.1016/j.cub.2003.10.062}}</ref><ref>{{citecytuj journalpismo | vauthors = Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D | titletytuł = Spatial regulation of developmental signaling by a serpin | journalczasopismo = Developmental Cell | volumewolumin = 5 | issuewydanie = 6 | stronys = 945–50 | datedata = December 2003 | pmid = 14667416 | doi = 10.1016/S1534-5807(03)00338-1}}</ref>. In ''Tenebrio molitor'' (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade<ref name="Jiang_2011">{{citecytuj journalpismo | vauthors = Jiang R, Zhang B, Kurokawa K, So YI, Kim EH, Hwang HO, Lee JH, Shiratsuchi A, Zhang J, Nakanishi Y, Lee HS, Lee BL | titletytuł = 93-kDa twin-domain serine protease inhibitor (Serpin) has a regulatory function on the beetle Toll proteolytic signaling cascade | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 286 | issuewydanie = 40 | strony = 35087–95 | datedata = October 2011 | pmid = 21862574 | pmc = 3186399 | doi = 10.1074/jbc.M111.277343}}</ref>.

The genome of the [[nematode]] worm ''[[Caenorhabditis elegans|C. elegans]]'' contains 9&nbsp;serpins, all of which lack signal sequences and so are likely intracellular<ref name="elegans1">{{citecytuj journalpismo | vauthors = Pak SC, Kumar V, Tsu C, Luke CJ, Askew YS, Askew DJ, Mills DR, Brömme D, Silverman GA | titletytuł = SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 279 | issuewydanie = 15 | stronys = 15448–59 | datedata = April 2004 | pmid = 14739286 | doi = 10.1074/jbc.M400261200}}</ref>. However, only&nbsp;5 of these serpins appear to function as protease inhibitors<ref name="elegans1"/>. One, SRP-6, performs a protective function and guards against stress-induced [[calpain]]-associated lysosomal disruption. Further, SRP-6 inhibits lysosomal cysteine proteases released after lysosomal rupture. Accordingly, worms lacking SRP-6 are sensitive to stress. Most notably, SRP-6 knockout worms die when placed in water (the hypo-osmotic stress lethal phenotype or Osl). It has therefore been suggested that lysosomes play a general and controllable role in determining cell fate<ref>{{citecytuj journalpismo | vauthors = Luke CJ, Pak SC, Askew YS, Naviglia TL, Askew DJ, Nobar SM, Vetica AC, Long OS, Watkins SC, Stolz DB, Barstead RJ, Moulder GL, Brömme D, Silverman GA | titletytuł = An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury | journalczasopismo = Cell | volumewolumin = 130 | issuewydanie = 6 | strony = 1108–19 | datedata = September 2007 | pmid = 17889653 | pmc = 2128786 | doi = 10.1016/j.cell.2007.07.013}}</ref>.

[[Plant]] serpins were amongst the first members of the superfamily that were identified<ref>{{citecytuj journalpismo | vauthors = Hejgaard J, Rasmussen SK, Brandt A, SvendsenI | titletytuł = Sequence homology between barley endosperm protein Z and protease inhibitors of the alpha-1-antitrypsin family | journalczasopismo = FEBS Lett. | volumewolumin = 180 | issuewydanie = 1 | rok = 1985 | stronys = 89–94 | doi = 10.1016/0014-5793(85)80238-6}}</ref>. The serpin barley protein Z is highly abundant in barley grain, and one of the major protein components in beer. The genome of the model plant, ''[[Arabidopsis thaliana]]'' contain 18&nbsp;serpin-like genes, although only&nbsp;8 of these are full-length serpin sequences.

Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases ''in vitro'', the best-studied example being barley serpin Zx (BSZx), which is able to inhibit trypsin and chymotrypsin as well as several blood coagulation factors<ref>{{citecytuj journalpismo | vauthors = Dahl SW, Rasmussen SK, Petersen LC, Hejgaard J | titletytuł = Inhibition of coagulation factors by recombinant barley serpin BSZx | journalczasopismo = FEBS Letters | volumewolumin = 394 | issuewydanie = 2 | strony = 165–8 | datedata = September 1996 | pmid = 8843156 | doi = 10.1016/0014-5793(96)00940-4}}</ref>. However, close relatives of chymotrypsin-like serine proteases are absent in plants. The RCL of several serpins from wheat grain and rye contain poly-Q repeat sequences similar to those present in the [[prolamin]] storage proteins of the endosperm<ref>{{citecytuj journalpismo | vauthors = Hejgaard J | titletytuł = Inhibitory serpins from rye grain with glutamine as P1 and P2 residues in the reactive center | journalczasopismo = FEBS Letters | volumewolumin = 488 | issuewydanie = 3 | stronys = 149–53 | datedata = January 2001 | pmid = 11163762 | doi = 10.1016/S0014-5793(00)02425-X}}</ref><ref>{{citecytuj journalpismo | vauthors = Ostergaard H, Rasmussen SK, Roberts TH, Hejgaard J | titletytuł = Inhibitory serpins from wheat grain with reactive centers resembling glutamine-rich repeats of prolamin storage proteins. Cloning and characterization of five major molecular forms | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 275 | issuewydanie = 43 | strony = 33272–9 | datedata = October 2000 | pmid = 10874043 | doi = 10.1074/jbc.M004633200}}</ref>. It has therefore been suggested that plant serpins may function to inhibit proteases from insects or microbes that would otherwise digest grain storage proteins. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin (CmPS-1)<ref name="plant">{{citecytuj journalpismo | vauthors = Yoo BC, Aoki K, Xiang Y, Campbell LR, Hull RJ, Xoconostle-Cázares B, Monzer J, Lee JY, Ullman DE, Lucas WJ | titletytuł = Characterization of cucurbita maxima phloem serpin-1 (CmPS-1). A developmentally regulated elastase inhibitor | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 275 | issuewydanie = 45 | stronys = 35122–8 | datedata = November 2000 | pmid = 10960478 | doi = 10.1074/jbc.M006060200}}</ref> and cucumber plants<ref>{{citecytuj journalpismo | vauthors = la Cour Petersen M, Hejgaard J, Thompson GA, Schulz A | titletytuł = Cucurbit phloem serpins are graft-transmissible and appear to be resistant to turnover in the sieve element-companion cell complex | journalczasopismo = Journal of Experimental Botany | volumewolumin = 56 | issuewydanie = 422 | strony = 3111–20 | datedata = December 2005 | pmid = 16246856 | doi = 10.1093/jxb/eri308}}</ref><ref>{{citecytuj journalpismo | vauthors = Roberts TH, Hejgaard J | titletytuł = Serpins in plants and green algae | journalczasopismo = Functional & Integrative Genomics | volumewolumin = 8 | issuewydanie = 1 | stronys = 1–27 | datedata = February 2008 | pmid = 18060440 | doi = 10.1007/s10142-007-0059-2}}</ref>. Although an inverse correlation between up-regulation of CmPS-1 expression and aphid survival was observed, ''in vitro'' feeding experiments revealed that recombinant CmPS-1 did not appear to affect insect survival<ref name="plant"/>.

Alternative roles and protease targets for plant serpins have been proposed. The ''Arabidopsis'' serpin, AtSerpin1 (At1g47710; {{PDB2|3LE2}}), mediates set-point control over programmed cell death by targeting the 'Responsive to Desiccation-21' (RD21) papain-like cysteine protease<ref name="Lampl_2010"/><ref>{{citecytuj journalpismo | vauthors = Lampl N, Alkan N, Davydov O, Fluhr R | titletytuł = Set-point control of RD21 protease activity by AtSerpin1 controls cell death in Arabidopsis | journalczasopismo = The Plant Journal | volumewolumin = 74 | issuewydanie = 3 | strony = 498–510 | datedata = May 2013 | pmid = 23398119 | doi = 10.1111/tpj.12141}}</ref>. AtSerpin1 also inhibits [[metacaspase]]-like proteases ''in vitro''<ref name="Vercammen_2006"/>. Two other ''Arabidopsis'' serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage<ref>{{citecytuj journalpismo | vauthors = Ahn JW, Atwell BJ, Roberts TH | titletytuł = Serpin genes AtSRP2 and AtSRP3 are required for normal growth sensitivity to a DNA alkylating agent in Arabidopsis | journalczasopismo = BMC Plant Biology | volumewolumin = 9 | stronys = 52 | rok = 2009 | pmid = 19426562 | pmc = 2689219 | doi = 10.1186/1471-2229-9-52}}</ref>.

Predicted serpin genes are sporadically distributed in [[prokaryote]]s. ''In vitro'' studies on some of these molecules have revealed that they are able to inhibit proteases, and it is suggested that they function as inhibitors ''in vivo''. Several prokaryote serpins are found in [[extremophile]]s. Accordingly, and in contrast to mammalian serpins, these molecules possess elevated resistance to heat denaturation<ref>{{citecytuj journalpismo | vauthors = Irving JA, Cabrita LD, Rossjohn J, Pike RN, Bottomley SP, Whisstock JC | titletytuł = The 1.5 A crystal structure of a prokaryote serpin: controlling conformational change in a heated environment | journalczasopismo = Structure | volumewolumin = 11 | issuewydanie = 4 | strony = 387–97 | datedata = April 2003 | pmid = 12679017 | doi = 10.1016/S0969-2126(03)00057-1}}</ref><ref>{{citecytuj journalpismo | vauthors = Fulton KF, Buckle AM, Cabrita LD, Irving JA, Butcher RE, Smith I, Reeve S, Lesk AM, Bottomley SP, Rossjohn J, Whisstock JC | titletytuł = The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 280 | issuewydanie = 9 | stronys = 8435–42 | datedata = March 2005 | pmid = 15590653 | doi = 10.1074/jbc.M410206200}}</ref>. The precise role of most bacterial serpins remains obscure, although ''[[Clostridium thermocellum]]'' serpin localises to the [[cellulosome]]. It is suggested that the role of cellulosome-associated serpins may be to prevent unwanted protease activity against the cellulosome<ref name="thermo2">{{citecytuj journalpismo | vauthors = Kang S, Barak Y, Lamed R, Bayer EA, Morrison M | titletytuł = The functional repertoire of prokaryote cellulosomes includes the serpin superfamily of serine proteinase inhibitors | journalczasopismo = Molecular Microbiology | volumewolumin = 60 | issuewydanie = 6 | strony = 1344–54 | datedata = June 2006 | pmid = 16796673 | doi = 10.1111/j.1365-2958.2006.05182.x}}</ref>.

Serpins are also expressed by [[virus]]es as a way to evade the host's immune defense<ref name="Turner_2002">{{citecytuj journalpismo | vauthors = Turner PC, Moyer RW | titletytuł = Poxvirus immune modulators: functional insights from animal models | journalczasopismo = Virus Research | volumewolumin = 88 | issuewydanie = 1-2 | stronys = 35–53 | datedata = September 2002 | pmid = 12297326 | doi = 10.1016/S0168-1702(02)00119-3}}</ref>. In particular, serpins expressed by [[Poxviridae|pox viruses]], including [[Cowpox|cow pox]] (vaccinia) and [[Rabbitpox|rabbit pox]] (myxoma), are of interest because of their potential use as novel therapeutics for immune and inflammatory disorders as well as transplant therapy<ref name="Richardson_2006">{{citecytuj journalpismo | vauthors = Richardson J, Viswanathan K, Lucas A | titletytuł = Serpins, the vasculature, and viral therapeutics | journalczasopismo = Frontiers in Bioscience | volumewolumin = 11 | issuewydanie = | strony = 1042–56 | rok = 2006 | pmid = 16146796 | doi = 10.2741/1862}}</ref><ref name="Jiang_2007">{{citecytuj journalpismo | vauthors = Jiang J, Arp J, Kubelik D, Zassoko R, Liu W, Wise Y, Macaulay C, Garcia B, McFadden G, Lucas AR, Wang H | titletytuł = Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment | journalczasopismo = Transplantation | volumewolumin = 84 | issuewydanie = 9 | stronys = 1158–67 | datedata = November 2007 | pmid = 17998872 | doi = 10.1097/01.tp.0000286099.50532.b0 | subscription = yes}}</ref>. Serp1 suppresses the toll-mediated innate immune response and allows indefinite cardiac [[Allotransplantation|allograft]] survival in rats.<ref name="Richardson_2006"/><ref name="Dai_2003">{{citecytuj journalpismo | vauthors = Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas A | titletytuł = Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury | journalczasopismo = The Journal of Biological Chemistry | volumewolumin = 278 | issuewydanie = 20 | strony = 18563–72 | datedata = May 2003 | pmid = 12637546 | doi = 10.1074/jbc.M209683200}}</ref> Crma and Serp2 are both cross-class inhibitors and target both serine (granzyme B; albeit weakly) and cysteine proteases (caspase&nbsp;1 and caspase&nbsp;8)<ref name="Turner_1999">{{citecytuj journalpismo | vauthors = Turner PC, Sancho MC, Thoennes SR, Caputo A, Bleackley RC, Moyer RW | titletytuł = Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1beta-converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus-infected cells | journalczasopismo = Journal of Virology | volumewolumin = 73 | issuewydanie = 8 | stronys = 6394–404 | datedata = August 1999 | pmid = 10400732 | pmc = 112719 | doi =}}</ref><ref name="Munuswamy-Ramanujam_2006">{{citecytuj journalpismo | vauthors = Munuswamy-Ramanujam G, Khan KA, Lucas AR | titletytuł = Viral anti-inflammatory reagents: the potential for treatment of arthritic and vasculitic disorders | journalczasopismo = Endocrine, Metabolic & Immune Disorders Drug Targets | volumewolumin = 6 | issuewydanie = 4 | strony = 331–43 | datedata = December 2006 | pmid = 17214579 | doi = 10.2174/187153006779025720}}</ref>. In comparison to their mammalian counterparts, viral serpins contain significant deletions of elements of secondary structure. Specifically, crmA lacks the D-helix as well as significant portions of the A- and E-helices<ref name="Renatus_2000">{{citecytuj journalpismo | vauthors = Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS | titletytuł = Crystal structure of the apoptotic suppressor CrmA in its cleaved form | journalczasopismo = Structure | volumewolumin = 8 | issuewydanie = 7 | stronys = 789–97 | datedata = 2000 | pmid = 10903953 | doi = 10.1016/S0969-2126(00)00165-9}}</ref>.