reticulum. protease-inhibition is thought to be the ancestral function, with non-inhibitory members the results of evolutionary neofunctionalisation of the structure. the s to r conformational change has also been adapted by some binding serpins to regulate affinity for their targets. distribution human the human genome encodes 16 serpin clades, termed serpina through serpinp, including 29 inhibitory and 7 non-inhibitory serpin proteins. the human serpin naming system is based upon a phylogenetic analysis of approximately 500 serpins from 2001, with proteins named serpinxy, where x is the clade of the protein and y the number of the protein within that clade. the functions of human serpins have been determined by a combination of biochemical studies, human genetic disorders, and knockout mouse models. table of human serpins gene name common name localisation function / activity effect of deficiency human disease chromosomal location protein structure serpina1 α1-antitrypsin extracellular inhibitor of human neutrophil elastase. the c-terminal fragment of cleaved serpina1 may inhibit hiv-1 infection. deficiency results in emphysema, polymerisation results in cirrhosis (serpinopathy). 14q32.1 1qlp​, 7api​, 1d5s​ serpina2 antitrypsin-related protein extracellular possible pseudogene. 14q32.1 serpina3 α1-antichymotrypsin extracellular inhibitor of cathepsin g. additional roles in chromatin condensation in hepatic cells. mis-regulation results in alzheimer's disease (serpinopathy). 14q32.1 1yxa​, 2ach​ serpina4 kallistatin extracellular inhibitor of kallikrein, regulator of vascular function. depletion in hypertensive rats exacerbates renal and cardiovascular injury. 14q32.1 serpina5 protein c inhibitor extracellular inhibitor of active protein c. intracellular role in preventing phagocytosis of bacteria. knockout in male mice causes infertility. accumulation occurs in chronic active plaques in multiple sclerosis. 14q32.1 2ol2​, 3b9f​ serpina6 transcortin extracellular non-inhibitory. cortisol binding. deficiency associated with chronic fatigue. 14q32.1 2v6d​, 2vdx​, 2vdy​ serpina7 thyroxine-binding globulin extracellular non-inhibitory. thyroxine binding. deficiency causes hypothyroidism. xq22.2 2ceo​, 2riv​, 2riw​ serpina8 angiotensinogen extracellular non-inhibitory, cleavage by renin results in release of angiotensin i. knockout in mice causes hypotension. variants linked to hypertension. 1q42-q43 2x0b​, 2wxw​, 2wxx​, 2wxy​, 2wxz​, 2wy0​, 2wy1​ serpina9 centerin / gcet1 extracellular inhibitory, maintenance of naive b cells. strongly expressed in most b-cell lymphomas. 14q32.1 serpina10 protein z-related protease inhibitor extracellular binds protein z and inactivates factor xa and factor xia. 14q32.1 3f1s​, 3h5c​ serpina11 – probably extracellular unknown 14q32.13 serpina12 vaspin extracellular inhibitor of kallikrein-7. insulin-sensitizing adipocytokine. high plasma levels associated with type ii diabetes. 14q32.1 4if8​ serpina13 – probably extracellular unknown 14q32 serpinb1 monocyte neutrophil elastase inhibitor intracellular inhibitor of neutrophil elastase. knockout in mice causes neutrophil survival defect and immune deficiency. 6p25 1hle​ serpinb2 plasminogen activator inhibitor-2 intracellular/extracellular inhibitor of extracellular upa. intracellular function unclear, but may protect against viral infection. deficiency in mice reduces immune response to nematode infection. knockout in mice causes no obvious phenotype. 18q21.3 1by7​ serpinb3 squamous cell carcinoma antigen-1 (scca-1) intracellular inhibitor of papain-like cysteine proteases and cathepsins k, l and s. knockout in mice of serpinb3a (the murine homolog of both human serpinb3 and serpinb4) have reduced mucus production in a murine model of asthma. 18q21.3 2zv6​ serpinb4 squamous cell carcinoma antigen-2 (scca-2) intracellular inhibitor of chymotrypsin-like serine proteases, cathepsin g and chymase. knockout in mice of serpinb3a (the murine homolog of both human serpinb3 and serpinb4) have reduced mucus production in a murine model of asthma. 18q21.3 serpinb5 maspin intracellular non-inhibitory, function unclear (see also maspin) knockout in mice originally reported as lethal, but subsequently shown to have no obvious phenotype. expression may be a prognostic indicator that reflects expression of a neighbouring tumour suppressor gene (the phosphatase phlpp1). 18q21.3 1wz9​ serpinb6 pi-6 intracellular inhibitor of cathepsin g. knockout in mice causes hearing loss and mild neutropenia. deficiency associated with hearing loss. 6p25 serpinb7 megsin intracellular involved in megakaryocyte maturation. over-expression in mice causes kidney disease. knockout in mice does not cause histological abnormalities. mutations associated with nagashima-type palmoplantar keratosis. 18q21.3 serpinb8 pi-8 intracellular possible inhibitor of furin. 18q21.3 serpinb9 pi-9 intracellular inhibitor of the cytotoxic granule protease granzyme b. knockout in mice causes immune dysfunction. 6p25 serpinb10 bomapin intracellular unknown knockout in mice causes no obvious phenotype (c57/bl6; lab strain bc069938). 18q21.3 serpinb11 intracellular unknown murine serpinb11 is an active inhibitor whereas the human orthalogue is inactive. deficiency in ponies is associated with hoof wall separation disease. 18q21.3 serpinb12 yukopin intracellular unknown 18q21.3 serpinb13 hurpin/headpin intracellular inhibitor of papain-like cysteine proteases. 18q21.3 serpinc1 antithrombin extracellular inhibitor of coagulation, specifically factor x, factor ix and thrombin. knockouts in mice are lethal. deficiency results in thrombosis and other clotting disorders (serpinopathy). 1q23-q21 2ant​, 2znh​, 1azx​, 1tb6​, 2gd4​, 1t1f​ serpind1 heparin cofactor ii extracellular inhibitor of thrombin. knockouts in mice are lethal. 22q11 1jmj​, 1jmo​ serpine1 plasminogen activator inhibitor 1 extracellular inhibitor of thrombin, upa and tpa. 7q21.3-q22 1dvn​, 1oc0​ serpine2 glia derived nexin / protease nexin i extracellular inhibitor of upa and tpa. abnormal expression leads to male infertility. knockout in mice causes epilepsy. 2q33-q35 4dy0​ serpinf1 pigment epithelium derived factor extracellular non-inhibitory, potent anti-angiogenic molecule. pedf has been reported to bind the glycosaminoglycan hyaluronan. knockout in mice affects the vasculature and mass of the pancreas and the prostate. promotes notch–dependent renewal of adult periventricular neural stem cells. mutations in humans cause osteogenesis imperfecta type vi. 17p13.3 1imv​ serpinf2 α2-antiplasmin extracellular inhibitor of plasmin, inhibitor of fibrinolysis. knockouts in mice show increased mice show increased fibrinolysis but no bleeding disorder. deficiency causes a rare bleeding disorder. 17pter-p12 2r9y​ serping1 complement 1-inhibitor extracellular inhibitor of c1 esterase. several polymorphisms associated with macular degeneration and hereditary angeoedema. 11q11-q13.1 2oay​ serpinh1 47 kda heat shock protein (hsp47) intracellular non-inhibitory, molecular chaperone in collagen folding. knockouts in mice are lethal. mutation in humans causes severe osteogenesis imperfecta. 11p15 4axy​ serpini1 neuroserpin extracellular inhibitor of tpa, upa and plasmin. mutation causes fenib dementia (serpinopathy). 3q26 1jjo​, 3fgq​, 3f5n​, 3f02​ serpini2 pancpin extracellular unknown deficiency in mice causes pancreatic insufficiency via acinar cell loss. 3q26 specialised mammalian serpins many mammalian 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 serpins. 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. 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. insect the drosophila melanogaster genome contains 29 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. 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 chromosomes. thirteen of the drosophila serpins occur as isolated genes in the genome (including serpin-27a, see below), with the remaining 16 organised into five gene clusters that occur at chromosome positions 28d (2 serpins), 42d (5 serpins), 43a (4 serpins), 77b (3 serpins) and 88e (2 serpins). 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 dorsoventral patterning. easter functions to cleave spätzle (a chemokine-type ligand), which results in toll-mediated signaling. as well as its central role in embryonic patterning, toll signaling is also important for the innate immune response in insects. accordingly, serpin-27a also functions to control the insect immune response. in tenebrio molitor (a large beetle), a protein (spn93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade. nematode the genome of the nematode worm c. elegans contains 9 serpins, all of which lack signal sequences and so are likely intracellular. however, only 5 of these serpins appear to function as protease inhibitors. 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. plant plant serpins were amongst the first members of the superfamily that were identified. 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 serpin-like genes, although only 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. 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. 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) and cucumber plants. 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. alternative roles and protease targets for plant serpins have been proposed. the arabidopsis serpin, atserpin1 (at1g47710; 3le2​), mediates set-point control over programmed cell death by targeting the 'responsive to desiccation-21' (rd21) papain-like cysteine protease. atserpin1 also inhibits metacaspase-like proteases in vitro. two other arabidopsis serpins, atsrp2 (at2g14540) and atsrp3 (at1g64030) appear to be involved in responses to dna damage. fungal a single fungal serpin has been characterized to date: celpin from piromyces spp. strain e2. piromyces is a genus of anaerobic fungi found in the gut of ruminants and is important for digesting plant material. celpin is predicted to be inhibitory and contains two n-terminal dockerin domains in addition to its serpin domain. dockerins are commonly found in proteins that localise to the fungal cellulosome, a large extracellular multiprotein complex that breaks down cellulose. it is therefore suggested that celpin may protect the cellulosome against plant proteases. certain bacterial serpins similarly localize to the cellulosome. prokaryotic predicted serpin genes are sporadically distributed in prokaryotes. 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 extremophiles. accordingly, and in contrast to mammalian serpins, these molecules possess elevated resistance to heat denaturation. 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. viral serpins are also expressed by viruses as a way to evade the host's immune defense. in particular, serpins expressed by pox viruses, including cow pox (vaccinia) and rabbit pox (myxoma), are of interest because of their potential use as novel therapeutics for immune and inflammatory disorders as well as transplant therapy. serp1 suppresses the tlr-mediated innate immune response and allows indefinite cardiac allograft survival in rats. crma and serp2 are both cross-class inhibitors and target both serine (granzyme b; albeit weakly) and cysteine proteases (caspase 1 and caspase 8). 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.