Email updates

Keep up to date with the latest news and content from Human Genomics and BioMed Central.

Open Access Highly Accessed Gene family update

Update of the human and mouse SERPIN gene superfamily

Claire Heit1, Brian C Jackson1, Monica McAndrews2, Mathew W Wright3, David C Thompson4, Gary A Silverman5, Daniel W Nebert6* and Vasilis Vasiliou1*

Author Affiliations

1 Department of Pharmaceutical Sciences, Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA

2 Mouse Genome Informatics, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA

3 HUGO Gene Nomenclature Committee (HGNC), European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK

4 Department of Clinical Pharmacy, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA

5 Department of Pediatrics and Cell Biology, University of Pittsburgh School of Medicine, Children's Hospital of UPMC, Pittsburgh, PA 15212, USA

6 Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA

For all author emails, please log on.

Human Genomics 2013, 7:22  doi:10.1186/1479-7364-7-22


The electronic version of this article is the complete one and can be found online at: http://www.humgenomics.com/content/7/1/22


Received:3 September 2013
Accepted:15 October 2013
Published:30 October 2013

© 2013 Heit et al.; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The serpin family comprises a structurally similar, yet functionally diverse, set of proteins. Named originally for their function as serine proteinase inhibitors, many of its members are not inhibitors but rather chaperones, involved in storage, transport, and other roles. Serpins are found in genomes of all kingdoms, with 36 human protein-coding genes and five pseudogenes. The mouse has 60 Serpin functional genes, many of which are orthologous to human SERPIN genes and some of which have expanded into multiple paralogous genes. Serpins are found in tissues throughout the body; whereas most are extracellular, there is a class of intracellular serpins. Serpins appear to have roles in inflammation, immune function, tumorigenesis, blood clotting, dementia, and cancer metastasis. Further characterization of these proteins will likely reveal potential biomarkers and therapeutic targets for disease.

Keywords:
Serpins; Serine protease inhibitor; Chaperone; Blood clotting; Thrombolysis; Complement; Cell death; Metastatic cancer

Introduction

Serpins represent the largest and most functionally diverse family of protease inhibitors. The name serpin originates from the first described function of this family, viz., serine proteinase inhibitors. In their native state, serpins exist as monomeric proteins. Most serpin family members inhibit serine proteinases of the chymotrypsin family [1], thereby inhibiting proteolytic cascades. However, some serpins exhibit functions unrelated to inhibition of catalytic activity, such as hormone transport and other mechanisms.

Approximately 1,500 serpin sequences have been identified; they are found in the genomes of all five kingdoms [2]. There are 36 identified human putatively functional protein-coding genes [3]. The serpin superfamily is divided into groups called clades according to their sequence similarity. Clades are classified as A–P, with clades A–I representing human serpins [4].

Serpins have well-conserved secondary structures with an exposed reactive center loop (RCL) (Figure 1), which interacts with the protease active site to inhibit protease activity [5]. The ability for serpins to undergo conformational change is crucial for their function, in which serpins act via a suicide substrate inhibitory mechanism [2,4]. Although most serpins selectively inhibit serine proteases, some inhibit cysteine proteases, such as caspases and cathespins; others perform hormone transport and blood pressure regulation [4]. Serpins play important physiological roles in hormone transport, corticosteroid binding, coagulation, and blood pressure regulation.

thumbnailFigure 1. Native SERPINA1. Native SERPINA1 with labeled structural elements: β sheet a and reactive center loop (RCL); α helices in red, β sheets in turquoise, turns in green. (Adapted from PDB 1HP7).

Serpin nomenclature

Initially named for tissue location or function (Table 1), a nomenclature committee convened in 1999 with the goal of standardizing serpin gene nomenclature [4]. ‘SERPIN’ was designated as the gene symbol for humans and other species because it is well known and used in the literature and as a keyword [4]. Serpins were not named for activity or function due to the diversity of member structure and tissue distribution. In 2005, proteinase in human gene names was replaced with the term peptidase; however, ‘serpin’ remains the stem because the name was designated prior to this change. The current classification of serpins involves division into clades that are based on phylogenetic relationships (Figure 2). There are 16 clades labeled A–P. Human serpins are represented in the first nine clades (i.e., A–I), with a variety of members being in each clade. Clades are phylogenetically unique and it is important to recognize that no relationships between the clade letters are implied by their order [4]. Some serpins are classified as orphans because they do not group with any other clade. It is likely that they will form clades as new serpins are identified. An example to help illustrate the nomenclature would be α-1-antitrypsin. This was assigned to the first clade, giving it the symbol SERPINA1 with the ‘A’ referencing the clade and the ‘1’ referencing the gene number within the clade [4].

Table 1. SERPIN aliases and function

thumbnailFigure 2. SERPIN phylogenetic tree. Phylogenetic tree of human and mouse serpin proteins. Protein sequences were aligned using TCOFFEE and analysed using neighbour-joining methods with 10,000 bootstrap replicates in the Phylip package.

Structure function

Serpins have a metastable structure that is required for their function. It consists of a highly conserved secondary structure with three β-sheets (A, B, and C), nine α-helices and a RCL (Figure 1), which serve as bait for target proteases [4,6]. Well-conserved throughout the serpin family, the tertiary structure of scaffold allows for a conformational change critical to protease inhibitor activity [4]. In their native state, serpins exist as monomeric proteins. A serpin molecule consists of a single 330- to 500-amino acid polypeptide chain that has conserved secondary helices and sheets. To inhibit proteolytic activity, the serpin acts as a suicide substrate for the protease [4]. This is accomplished by the RCL of the serpin interacting with the protease's active site [6].

Serpins can exist in several forms, viz., active, latent, cleaved, delta, and polymeric. Each form is defined by the RCL, which is the moiety required for inhibitory activity. The active form (or the native state) has an exposed RCL that allows it to interact with the protease. The RCL forms an exposed extension located above the molecule. Following proteolysis, the amino acid terminus of the RCL inserts into the A β sheet forming a fourth strand. This process is called the ‘stressed (S) to relaxed (R) transition’ [3] used to inhibit proteases, resulting in the cleaved form. The cleaved form is necessary for inhibition of proteases resulting in an irreversible covalent complex with the target protease thus inactivating both the serpin and the target. Some serpins bind cofactors and/or glycosaminoglycans to maximize protease inhibition, which can vastly increase inhibitory potential [7].

The native form of serpins has low thermal stability indicating that it is not the most stable conformation; rather, native serpins are metastable. However, not all serpins undergo this transition. Serpins can transition to the latent form from the active form and back to the active form from the latent form. The latent form does not possess inhibitory activity but it can convert to the active form through denaturation and refolding [4]. Consequently, it can be considered a control mechanism in regulating homeostasis for certain serpins [3]. Alternatively, the latent state caused by a mutation can be pathological [3].

The delta form is an intermediate conformation between latent and native state where the RCL inserts into the A β sheet and one of the helices unwinds and completes hydrogen bonding of the β sheet [3]. Little is known about the function of this conformation; however, it is likely that this favors polymeric or latent conformation transition rather than native. The polymeric form has a loop sheet mechanism whereby the RCL that would be inserted into the same serpin is instead inserted into the A β sheet of another serpin forming a long chain of these molecules [3]. However, this mechanism of polymerization has recently been challenged in favor of that of a domain-swapping model [8]. Serpins are unique in that their native state (active form) is not the most kinetically stable; rather, it is ‘metastable’. By incorporating the RCL into their A β sheet, either by cleavage for inhibition of target protease or spontaneous latency, they become more stable [9]. For an excellent minireview on kinetics of serpins, see Silverman et al. [4].

Evolution

Whereas serpins have highly conserved secondary and tertiary structures upon which they are grouped, they often share little amino acid sequence similarity. They do, however, share a highly conserved core, especially in the shutter domain including Ser56 and Ser53 [10], which is thought to be critical in determining tertiary structure and conformational flexibility.

Due to the numerous, yet distinct, processes regulated by serpins and their widespread functions, serpins offer a unique perspective for protein evolution. Members of the serpin family tend to group phylogenetically by species rather than by function. Therefore, evolution of the serpin family was likely driven by speciation to fill their physiological roles rather than by coevolution with the serine proteases (which group by function) [10]. Numerous serpin genes are also found in clusters on the same chromosomes, reflecting earlier gene-duplication events and potentially indicating a common precursor [11,12]. Interestingly, these genes are functionally divergent, despite their chromosomal proximity [7]. In addition, serpins have distinct patterns of introns and exons. These patterns may contain information regarding phylogenetic signals and be evolutionarily related based on relative intron positioning [13,14].

The distribution of serpins in eukaryotes suggests that they arose early in eukaryotic evolution [1]. Extensive gene clustering indicates that numerous serpins in close proximity on the same chromosome may have arisen as a result of duplications from a common precursor [12]; however, the evolution of these proximal genes gave way to vastly divergent functions.

Intracellular serpins of clade B are ancestral to most extracellular serpins [15,16] and each inhibitory serpin contains a highly conserved hinge region [16] within the RCL. Clade F serpins specifically share ancestry with a sea lamprey serpin. Clade P is specific to plant serpins which form a discrete clade. At the time of divergence between Viridiplantae and fungi/Metazoa groups, there was likely only one serpin gene [16]; however, the ancestral homolog from prokaryote or fungi has not yet been identified [16].

There are eight human serpin pseudogenes listed in Table 2. SERPINA15P has been named in succession for the A clade with the parent gene SERPINA6 according to Ensembl and SERPINE2 is the parent gene for SERPINE4P, again named in sequence of the E clade. There are ten mouse pseudogenes listed (Table 3) which remain uncharacterized.

Table 2. Human SERPIN genes

Table 3. Mouse Serpin genes

Methods

Protein sequences for human serpins were accessed from Uniprot through the HUGO Gene Nomenclature Committee website (http://www.genenames.org webcite). Sequences were retrieved from the National Center for Biotechnology Information (NCBI) gene database (http://www.ncbi.nlm.nih.gov/gene webcite) referenced through the HUGO Gene Nomenclature Committee website (http://www.genenames.org webcite) for humans and MGI website (http://www.informatics.jax.org webcite) for mouse. All sequences were aligned using the most accurate settings of T-Coffee (http://tcoffee.crg.cat/ webcite) and phylogenetic trees were constructed using neighbor-joining methods with 1000 replicate bootstrap in PHYLIP 3.69 (http://evolution.genetics.washington.edu/phylip.html webcite) (Figure 2). Expression data were determined using Genecards (http://www.genecards.org webcite) and alternative name information was determined using HGNC (http://www.genenames.org webcite) or MGI (http://www.informatics.jax.org webcite).

Human and mouse serpin isoforms

Clade A

Clade A serpins are classified as antitrypsin-like, extracellular proteins. They are the largest of the eight clades of extracellular serpins. The SERPINA clade has eleven human genes (1, 3–12) and two pseudogenes.

SERPINA1 is an inhibitory serpin formerly known as antitrypsin. It plays a role in the inhibition of neutrophil elastase [3,17].

SERPINA2 was initially classified as a pseudogene; however, recent evidence indicates that it produces an active transcript that encodes a protein located in the endoplasmic reticulum [18]. A study that sequenced SERPINA2 genes across multiple ethnic groups indicated that in addition to active SERPINA2 protein, there is a haplotype characterized by a partial deletion which has patterns suggestive of positive selection for loss-of-function of SERPINA2 protein. They suggest that the partial pseudogenization in humans may indicate an ongoing process of pseudogenization [19].

SERPINA3 is an inhibitory protein formerly known as antichymotrypsin. It inhibits chymotrypsin and cathepsin G [3,16]. This serpin is normally found in blood, liver, kidney, and lung.

SERPINA4 is an inhibitory protein formerly known as kallistatin (PI4), which inhibits kallikrein [20]. It is expressed in blood, liver, kidney, and heart.

SERPINA5, formerly a protein C inhibitor, inhibits active protein C. It is present in blood, kidney and liver.

SERPINA6 was formerly known as corticosteroid-binding globulin. It is a non-inhibitory protein that binds hormones, i.e., cortisol [16].

SERPINA7, formerly thyroxine-binding globulin, is involved in non-inhibitory thyroid hormone transport. It is expressed in blood, kidney, and heart.

SERPINA8 is now referred to as angiotensinogen (AGT), which is a hormone precursor. It has a distinct serpin domain (phylogenetically unrelated to other clade A members in the current analysis) and a distinct, smaller, agt domain. This particular serpin domain appears to be more closely associated with SERPINF and SERPING [21].

SERPINA9 appears to have a role in naïve B cell maintenance. Formerly called centerin, it is expressed in the plasma and liver.

SERPINA10 is an inhibitory protein responsible for inhibition of activated coagulation factors Z and XI [3]. Formerly known as protein Z-dependent proteinase inhibitor, it is expressed in blood and liver.

SERPINA11 is likely a pseudogene and is uncharacterized.

SERPINA12, formerly vaspin, inhibits kallikrein [22] and plays a role in insulin sensitivity [23]. It appears to be expressed in plasma, platelets, liver and heart.

In the mouse (Table 3), Serpina1 has been expanded to include six members, af. Serpina3 has been expanded to include nine members, ac and fn. The other clade a members are orthologous to human genes. Serpina8, now known as Agt in the mouse, is vital for the development and function of the renin-angiotensin system [24]. It is orthologous to AGT in humans.

Clade B

Clade B consists of intracellular serpins, including ov-serpins, which are ancestral to the extracellular serpins [16]. Members of this subfamily have shorter C and N termini than typical A members and also lack the secretory signal peptide sequence [4]. There are 13 human genes in clade B and one pseudogene. Serpins in clade B are important in inflammation and immune system function as well as mucous production [25]. SERPINB1, B6, B7, and B9 are involved in immune system function with roles in neutrophil and megakaryocyte development [26,27], as well as in the inhibition of the cytotoxic granule protease granzyme B [28]. SERPINB3 and its close homolog B4 are inhibitors that have roles in mucous production [29] and are expressed in epithelial tissues, such as tongue, tonsils, uterus, cervix, and vagina as well as in the upper respiratory tract and thymus [30].

Despite elusive function, SERPINB3 appears to have a role in apoptotic regulation and immunity, which implicates B3 in tumor metastasis and autoimmunity [30]. SERPINB5 has been shown to inhibit metastasis as a tumor suppressor in breast and prostate cancer [30,31]. In addition, multiple serpins in the B clade have been associated with oral squamous cell carcinoma, specifically SERPINB12, SERPINB13, SERPINB4, SERPINB3, SERPINB11, SERPINB7, and SERPINB2 [32]. Less is known about SERPINB10–B13. However, recent evidence points to a role for SERPINB13 in autoimmune diabetes progression and in inflammation [33].

SERPINB1 is an inhibitor of neutrophil elastase. It was formerly called monocyte neutrophil elastase inhibitor and is expressed ubiquitously.

SERPINB2 inhibits PLAU (uPA). It was formerly called plasminogen activator inhibitor 2 (PAI2) and is expressed in blood, kidney, and liver.

SERPINB3 is a cross-class inhibitor of cathepsin L and V [34]. Formerly referred to as squamous cell carcinoma antigen 1, it is expressed in blood, immune cells, kidney, lung, heart, and brain as well as numerous mucosal cells.

SERPINB4 was formerly known as squamous cell carcinoma antigen 2; it was discovered with SERPINB3 [25]. It is a cross-class inhibitor of cathepsin G and chymase [35] and is found in plasma, platelets, kidney, and heart, as well as saliva.

SERPINB5 is a non-inhibitory protein formerly called maspin. It is likely expressed in blood, kidney, liver, lung, as well as saliva.

SERPINB6, formerly called proteinase inhibitor 6 (PI6), is an inhibitor of granule protease, cathepsin G [36]. It is expressed ubiquitously.

SERPINB7 is involved in mesangial cell proliferation [37]. Formerly called megsin, it is expressed in blood and liver.

SERPINB8 is an inhibitory protein. Formerly called proteinase inhibitor 8 (PI8), it is expressed in blood and heart.

SERPINB9 is an inhibitory protein. Formerly called proteinase inhibitor 9 (PI9), it is expressed in blood, liver, lung, and heart.

SERPINB10 is an inhibitory protein involved in hematopoietic and myeloid development [37]. Formerly called bomapin, it expressed in blood and possibly in the brain.

SERPINB11 is a non-inhibitory serpin in human but retains trypsin inhibitory activity in mice [38]. It appears not to exhibit tissue-specific expression; however, it is expressed in HEK cells.

SERPINB12 is a trypsin inhibitor formerly known as yukopin [39]. It is expressed in blood, kidney, liver, heart, and brain.

SERPINB13, formerly known as hurpin, is expressed in blood, kidney, and saliva.

In clade b, mouse Serpinb1 has been expanded to include three members ac; Serpinb3 as well as Serpinb6 have each expanded to include four members, ad. In mice, Serpinb4 is not listed; however, it appears that SERPINB3 and SERPINB4 are equally related to Serpinb3a, Serpinb3b, Serpinb3c, and Serpinb3d, despite the initial theory that Serpinb3d is the mouse homolog of human SERPINB3 and Serpinb3c is the mouse homolog of SERPINB4. Serpinb9 has been expanded to seven members and one pseudogene. Interestingly, Serpinb11 is an active proteinase inhibitor, whereas the human ortholog is inactive.

Clade C

Serpin clade C consists of only one serpin member, SERPINC1, more commonly known as antithrombin. SERPINC1 inhibits coagulation factors IX and X [40]. It is expressed in blood, kidney, liver, lung, heart, brain, as well as saliva.

Serpinc1 gene encodes antithrombin and is orthologous to human SERPINC1.

Clade D

Clade D has one serpin member, SERPIND1, which is an extracellular protein also known as heparin cofactor II [41]. It is an inhibitor of thrombin [42] and is expressed in blood, kidney, liver, and heart.

Serpind1 encodes heparin cofactor II and is orthologous to SERPIND1.

Clade E

Clade E has three members, E1, E2, and E3, all of which are extracellular.

SERPINE1, also known as plasminogen activator inhibitor-1 (PAI1), inhibits thrombin. It is expressed in blood, liver, and heart.

SERPINE2 is a glial-derived nexin that is important in recovery of nerve structure and function [43]. It is expressed in blood, liver, kidney, and brain.

Little is known about the function of SERPINE3.

The mouse genes in clade e (Serpine1–3) are orthologous to human SERPINE1–3.

Clade F

There are two members in SERPIN clade F.

SERPINF1 (or pigment epithelium-derived factor (PEDF)) regulates angiogenesis and is an example of a non-inhibitory serpin. It is also thought to be a neurotrophic factor [16], and appears to be expressed in blood, liver, kidney, heart, and possibly lung.

SERPINF2, also known as α-2-antiplasmin, is an inhibitor of fibrinolysis. It is found in blood, kidney, liver, and heart.

Mouse Serpinf1 and f2 genes are orthologous to the human SERPINF1 and SERPINF2 genes, respectively.

Clade G

Clade G consists of one inhibitory serpin.

SERPING1 is a complement I esterase inhibitor [44] formerly called C1 inhibitor. It is expressed in blood, liver, kidney, lung, heart, and brain.

Mouse Serping1 encodes C1 inhibitor and is orthologous to SERPING1.

Clade H

Clade H consists of one member.

SERPINH1, also known as 47-kDa heat shock protein (HSP47), does not act as a proteinase inhibitor, but rather as a chaperone for collagen [45]. It is expressed in blood, liver and heart.

Mouse Serpinh1 encodes HSP47 and is orthologous to SERPINH1. Knockouts of Serpinh1 in mice are lethal [46] and missense mutations are associated with osteogenesis imperfecta [47].

Clade I

Clade I consists of two extracellular proteins. Serpins in clade I include the following.

SERPINI1 is a neuroserpin inhibitor of PLAT (tPA), PLAU (uPA), and plasmin [48]. It is expressed in liver and possibly plasma.

SERPINI2, previously known as pancipin, has an unknown protein target but may be involved in pancreatic dysfunction [49]. It is found in platelets and plasma as well as the heart.

The genes Serpini1 and Serpini2 encode mouse neuroserpin and pancipin, respectively. These are orthologous to SERPINI1 and SERPINI2 in the human.

Clades J–P

Clades jp represent viral, nematode, horseshoe crab, blood fluke, and plant serpins [16] and will not be described further in this update.

Serpins associated with disease

Serpin polymorphisms have been associated with in many disease states, including blood clotting disorders, emphysema, cirrhosis, and dementia [15,16,50] as well as tumorigenesis and metastasis.

Mutations in SERPINA1 result in a decrease in circulating α-1-antitrypsin which is associated with emphysema and hepatocellular carcinoma [51]. Serpins are implicated in regulation of the cardiovascular system. For example, SERPINA4 depletion is related to renal and cardiovascular injury [52], SERPINA8 variations are integral to the normal function of the renin-angiotensin system and have been found to regulate blood pressure [53], and a SERPINA10 polymorphism was found to increase the risk of venous thromboembolism [54,55]. SERPINA3 deficiency is associated with emphysema [56].

Many SERPINBs are implicated in immune function and dysfunction. In many of these cases, intracellular serpins cause autoimmune antibody production, inflammation, neutropenia, and cancer metastasis [25]. SERPINC1 deficiency has been correlated with autoimmune disease, especially in patients producing antinuclear antibodies, such as those with systemic lupus erythematosus [30]. Interestingly, a SERPINA6 polymorphism has been associated with chronic fatigue syndrome [57], which is thought to be an immune disorder. SERPINA7 deficiency is associated with hyperthyroidism, and high SERPINA12 levels have been associated with insulin resistance [23].

Mutations in SERPINH1, as well as in SERPINF1, are associated with osteogenesis imperfecta [47,58].

Serpins appear to influence protein aggregation. In this respect, SERPINI1 expression has been correlated with dementia [4]. In addition, SERPINA5 accumulation has been identified in plaques in multiple sclerosis [59] and SERPINA3 polymerization may accelerate onset and severity of Alzheimer's disease [30].

Many serpins have been implicated in cancer progression including SERPINBs (on the 18q21 locus) in oral squamous cell carcinoma [25]. Breast and prostate cancer metastases are also closely associated with SERPINB5 [60,61]. In addition, SERPINE1 appears to have a role in tumor progression [62] and metastasis [63]. Further, SERPINI2 may play a possible role in breast and pancreatic cancer metastasis [49]. Adult gliomas have significant associations with SERPINI1 [64], although its role is unknown. In addition, SERPINI1 has also been proposed as one of five biomarkers in hepatocellular carcinoma [65]. Another potential biomarker includes SERPINA9, which has been found to be strongly expressed in B cell lymphomas [66].

Mouse models of human disease

There are numerous mouse models used to study the role of SERPINs in disease. Some examples include knockout of Serpinag3 used in studying T cells in immunology [67], hepatic specific knockout of Serpinc1, which exhibits coagulopathy [68], and Agt knockout to study blood pressure regulation and the renin-angiotensin system where adipocyte-specific knockout of agt caused decreased systolic blood pressure [69]. Serpinb1 knockout mice show neutropenia [70].

Gene variants in SERPINS

A large number of human variants of serpin genes have been found. For example, NCBI's dbSNP database (http://www.ncbi.nlm.nih.gov/snp webcite) has 621 entries for SNPs of SERPINA1 alone (accessed October 2013). In addition, several groups have developed specific databases for individual SERPIN genes. These include databases for SERPINA1[71], SERPINC3[72], and SERPING1[73]. A number of pathologies in humans have been attributed to SERPIN gene variants, and often multiple deleterious mutations are known for each gene. Although a full listing of disease-causing SERPIN mutations is beyond the scope of this review, a sample of their scope is provided here. Mutations in the SERPINA1 gene have been linked with early-onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, and sometimes panniculitis and vasculitis [74,75]. SERPINA5 mutations have been linked with increased papillary thyroid cancer risk [76], and mutations in SERPINA10 have been linked to pregnancy complications [77]. Predisposition to familial venous thromboembolic disease has been linked to mutations in SERPINC1[78,79]. Finally, SNP variants for the SERPING1 gene have been shown to be associated with hereditary angioedema [80].

Conclusions

Serpins are a large class of diverse proteins, which contribute to numerous physiological and pathological conditions. Identification of serpins in immunological functions, pathology due to polymerization, and cancer metastasis underscores their diverse functions and physiological and pathological importance, and gene mutations often lead to loss-of-function and pathology in affected individuals. However, there is still much to learn about the functions and evolutionary development of serpins. Because of numerous biological functions and pathological states associated with serpins, further characterization of these proteins and mechanistic information will provide insight into potential biomarker identification and therapeutic targets.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

CH carried out the sequence alignments and drafted the manuscript. BJ participated in the sequence alignment and analysis. MM reviewed mouse gene/protein data and the nomenclature for accuracy and completeness. MW reviewed human gene/protein data and nomenclature for accuracy and completeness. DT, GS and DWN reviewed and edited the manuscript. VV designed the study and reviewed data and manuscript. All authors read and approved the final manuscript.

Acknowledgements

This work was supported, in part, by the following NIH grants: R24 AA022057, NIEHS P30 ES06096, HG000330, U41HG003345 and also by a Welcome Trust grant no. 099129/Z/12/Z. Fellowship assistance for BCJ (F31 AA020728) is acknowledged. We would like to thank Konstandinos Vasiliou for his assistance.

References

  1. Wright HT: Introns and higher-order structure in the evolution of serpins.

    J Mol Evol 1993, 36:136-143. Publisher Full Text OpenURL

  2. Potempa J, Korzus E, Travis J: The serpin superfamily of proteinase inhibitors: structure, function, and regulation.

    J Biol Chem 1994, 269:15957-15960. PubMed Abstract | Publisher Full Text OpenURL

  3. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC: An overview of the serpin superfamily.

    Genome Biol 2006, 7:216. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  4. Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC: The serpins are an expanding superfamily of structurally similar but functionally diverse proteins: evolution, mechanism of inhibition, novel functions, and a revised nomenclature.

    J Biol Chem 2001, 276:33293-33296. PubMed Abstract | Publisher Full Text OpenURL

  5. Schechter I, Berger A: On the size of the active site in proteases: I. Papain.

    Biochem Biophys Res Commun 1967, 27:157-162. PubMed Abstract | Publisher Full Text OpenURL

  6. Huber R, Carrell RW: Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins.

    Biochemistry-US 1989, 28:8951-8966. Publisher Full Text OpenURL

  7. Rein CM, Desai UR, Church FC: Serpin-glycosaminoglycan interactions.

    Methods Enzymol 2011, 501:105-137. PubMed Abstract | Publisher Full Text OpenURL

  8. Yamasaki M, Sendall TJ, Pearce MC, Whisstock JC, Huntington JA: Molecular basis of alpha1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer.

    EMBO Rep 2011, 12:1011-1017. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Huntington JA: Serpin structure, function and dysfunction.

    J Thromb Haemost 2011, 9(1):26-34. PubMed Abstract | Publisher Full Text OpenURL

  10. Krem MM, Di Cera E: Conserved ser residues, the shutter region, and speciation in serpin evolution.

    J Biol Chem 2003, 278:37810-37814. PubMed Abstract | Publisher Full Text OpenURL

  11. Billingsley GD, Walter MA, Hammond GL, Cox DW: Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1.

    Am J Hum Genet 1993, 52:343-353. PubMed Abstract | PubMed Central Full Text OpenURL

  12. Rollini P, Fournier RE: A 370-kb cosmid contig of the serpin gene cluster on human chromosome 14q32.1: molecular linkage of the genes encoding alpha 1-antichymotrypsin, protein C inhibitor, kallistatin, alpha 1-antitrypsin, and corticosteroid-binding globulin.

    Genomics 1997, 46:409-415. PubMed Abstract | Publisher Full Text OpenURL

  13. Long M, de Souza SJ, Gilbert W: Evolution of the intron-exon structure of eukaryotic genes.

    Curr Opin Genet Dev 1995, 5:774-778. PubMed Abstract | Publisher Full Text OpenURL

  14. Logsdon JM Jr, Stoltzfus A, Doolittle WF: Molecular evolution: recent cases of spliceosomal intron gain?

    Curr Biol 1998, 8:R560-R563. PubMed Abstract | Publisher Full Text OpenURL

  15. Clarke EP, Cates GA, Ball EH, Sanwal BD: A collagen-binding protein in the endoplasmic reticulum of myoblasts exhibits relationship with serine protease inhibitors.

    J Biol Chem 1991, 266:17230-17235. PubMed Abstract | Publisher Full Text OpenURL

  16. Irving JA, Pike RN, Lesk AM, Whisstock JC: Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function.

    Genome Res 2000, 10:1845-1864. PubMed Abstract | Publisher Full Text OpenURL

  17. Clemmensen SN, Jacobsen LC, Rorvig S, Askaa B, Christenson K, Iversen M, Jorgensen MH, Larsen MT, van Deurs B, Ostergaard O, Heegaard NH, Cowland JB, Borregaard N: Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis.

    Eur J Haematol 2011, 86:517-530. PubMed Abstract | Publisher Full Text OpenURL

  18. Marques PI, Ferreira Z, Martins M, Figueiredo J, Silva DI, Castro P, Morales-Hojas R, Simoes-Correia J, Seixas S: SERPINA2 is a novel gene with a divergent function from SERPINA1.

    PLoS One 2013, 8:e66889. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Seixas S, Suriano G, Carvalho F, Seruca R, Rocha J, Di Rienzo A: Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2.

    Mol Biol Evol 2007, 24:587-598. PubMed Abstract | Publisher Full Text OpenURL

  20. Chao J, Schmaier A, Chen LM, Yang Z, Chao L: Kallistatin, a novel human tissue kallikrein inhibitor: levels in body fluids, blood cells, and tissues in health and disease.

    J Lab Clin Med 1996, 127:612-620. PubMed Abstract | Publisher Full Text OpenURL

  21. Paterson MA, Horvath AJ, Pike RN, Coughlin PB: Molecular characterization of centerin, a germinal centre cell serpin.

    Biochem J 2007, 405:489-494. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  22. Heiker JT, Kloting N, Kovacs P, Kuettner EB, Strater N, Schultz S, Kern M, Stumvoll M, Bluher M, Beck-Sickinger AG: Vaspin inhibits kallikrein 7 by serpin mechanism.

    Cell Mol Life Sci 2013, 70:2569-2583. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  23. Teshigawara S, Wada J, Hida K, Nakatsuka A, Eguchi J, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Iseda I, Matsushita Y, Miyatake N, McDonald JF, Hotta K, Makino H: Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population.

    J Clin Endocrinol Metab 2012, 97:E1202-E1207. PubMed Abstract | Publisher Full Text OpenURL

  24. Hilgers KF, Norwood VF, Gomez RA: Angiotensin's role in renal development.

    Semin Nephrol 1997, 17:492-501. PubMed Abstract OpenURL

  25. Vidalino L, Doria A, Quarta S, Zen M, Gatta A, Pontisso P: SERPINB3, apoptosis and autoimmunity.

    Autoimmun Rev 2009, 9:108-112. PubMed Abstract | Publisher Full Text OpenURL

  26. Tsujimoto M, Tsuruoka N, Ishida N, Kurihara T, Iwasa F, Yamashiro K, Rogi T, Kodama S, Katsuragi N, Adachi M, Katayama T, Nakao M, Yamaichi K, Hashino J, Haruyama M, Miura K, Nakanishi T, Nakazato H, Teramura M, Mizoguchi H, Yamaguchi N: Purification, cDNA cloning, and characterization of a new serpin with megakaryocyte maturation activity.

    J Biol Chem 1997, 272:15373-15380. PubMed Abstract | Publisher Full Text OpenURL

  27. Miyata T, Inagi R, Nangaku M, Imasawa T, Sato M, Izuhara Y, Suzuki D, Yoshino A, Onogi H, Kimura M, Sugiyama S, Kurokawa K: Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion.

    J Clin Invest 2002, 109:585-593. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  28. Sun J, Bird CH, Sutton V, McDonald L, Coughlin PB, De Jong TA, Trapani JA, Bird PI: A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes.

    J Biol Chem 1996, 271:27802-27809. PubMed Abstract | Publisher Full Text OpenURL

  29. Sivaprasad U, Askew DJ, Ericksen MB, Gibson AM, Stier MT, Brandt EB, Bass SA, Daines MO, Chakir J, Stringer KF, Wert SE, Whitsett JA, Le Cras TD, Wills-Karp M, Silverman GA, Khurana Hershey GK: A nonredundant role for mouse serpinb3a in the induction of mucus production in asthma.

    J Allergy Clin Immunol 2011, 127:254-261.

    261 e251-256

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  30. Gatto M, Iaccarino L, Ghirardello A, Bassi N, Pontisso P, Punzi L, Shoenfeld Y, Doria A: Serpins, immunity and autoimmunity: old molecules, new functions.

    Clin Rev Allergy Immunol 2013, 45(2):267-280. PubMed Abstract | Publisher Full Text OpenURL

  31. Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R: Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.

    Science 1994, 263:526-529. PubMed Abstract | Publisher Full Text OpenURL

  32. Shiiba M, Nomura H, Shinozuka K, Saito K, Kouzu Y, Kasamatsu A, Sakamoto Y, Murano A, Ono K, Ogawara K, Uzawa K, Tanzawa H: Down-regulated expression of SERPIN genes located on chromosome 18q21 in oral squamous cell carcinomas.

    Oncol Rep 2010, 24:241-249. PubMed Abstract | Publisher Full Text OpenURL

  33. Baldzizhar R, Fedorchuk C, Jha M, Rathinam C, Henegariu O, Czyzyk J: Anti-serpin antibody-mediated regulation of proteases in autoimmune diabetes.

    J Biol Chem 2013, 288:1612-1619. PubMed Abstract | Publisher Full Text OpenURL

  34. Schick C, Pemberton PA, Shi GP, Kamachi Y, Cataltepe S, Bartuski AJ, Gornstein ER, Bromme D, Chapman HA, Silverman GA: Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis.

    Biochemistry-US 1998, 37:5258-5266. Publisher Full Text OpenURL

  35. Schick C, Kamachi Y, Bartuski AJ, Cataltepe S, Schechter NM, Pemberton PA, Silverman GA: Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase.

    J Biol Chem 1997, 272:1849-1855. PubMed Abstract | Publisher Full Text OpenURL

  36. Scott FL, Hirst CE, Sun J, Bird CH, Bottomley SP, Bird PI: The intracellular serpin proteinase inhibitor 6 is expressed in monocytes and granulocytes and is a potent inhibitor of the azurophilic granule protease, cathepsin G.

    Blood 1999, 93:2089-2097. PubMed Abstract | Publisher Full Text OpenURL

  37. Xia Y, Zhang Y, Shi W, Liu S, Chen Y, Liang X, Ye Z: Overexpression of megsin induces mesangial cell proliferation and excretion of type IV collagen in vitro.

    Cell Immunol 2011, 271:413-417. PubMed Abstract | Publisher Full Text OpenURL

  38. Askew DJ, Cataltepe S, Kumar V, Edwards C, Pace SM, Howarth RN, Pak SC, Askew YS, Bromme D, Luke CJ, Whisstock JC, Silverman GA: SERPINB11 Is a new noninhibitory intracellular serpin: common single nucleotide polymorphisms in the scaffold impair conformational change.

    J Biol Chem 2007, 282:24948-24960. PubMed Abstract | Publisher Full Text OpenURL

  39. Askew YS, Pak SC, Luke CJ, Askew DJ, Cataltepe S, Mills DR, Kato H, Lehoczky J, Dewar K, Birren B, Silverman GA: SERPINB12 is a novel member of the human ov-serpin family that is widely expressed and inhibits trypsin-like serine proteinases.

    J Biol Chem 2001, 276:49320-49330. PubMed Abstract | Publisher Full Text OpenURL

  40. Huntington JA: Shape-shifting serpins–advantages of a mobile mechanism.

    Trends Biochem Sci 2006, 31:427-435. PubMed Abstract | Publisher Full Text OpenURL

  41. Vicente CP, He L, Pavao MS, Tollefsen DM: Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice.

    Blood 2004, 104:3965-3970. PubMed Abstract | Publisher Full Text OpenURL

  42. Rau JC, Deans C, Hoffman MR, Thomas DB, Malcom GT, Zieske AW, Strong JP, Koch GG, Church FC: Heparin cofactor II in atherosclerotic lesions from the pathobiological determinants of atherosclerosis in youth (PDAY) study.

    Exp Mol Pathol 2009, 87:178-183. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Lino MM, Atanasoski S, Kvajo M, Fayard B, Moreno E, Brenner HR, Suter U, Monard D: Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush.

    J Neurosci 2007, 27:3677-3685. PubMed Abstract | Publisher Full Text OpenURL

  44. Beinrohr L, Harmat V, Dobo J, Lorincz Z, Gal P, Zavodszky P: C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease.

    J Biol Chem 2007, 282:21100-21109. PubMed Abstract | Publisher Full Text OpenURL

  45. Widmer C, Gebauer JM, Brunstein E, Rosenbaum S, Zaucke F, Drogemuller C, Leeb T, Baumann U: Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition.

    Proc Natl Acad Sci U S A 2012, 109:13243-13247. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  46. Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K: Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis.

    J Cell Biol 2000, 150:1499-1506. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  47. Christiansen HE, Schwarze U, Pyott SM, Al Swaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH: Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta.

    Am J Hum Genet 2010, 86:389-398. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  48. Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, Meins M, Sonderegger P: The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin.

    J Biol Chem 1998, 273:2312-2321. PubMed Abstract | Publisher Full Text OpenURL

  49. Ozaki K, Nagata M, Suzuki M, Fujiwara T, Miyoshi Y, Ishikawa O, Ohigashi H, Imaoka S, Takahashi E, Nakamura Y: Isolation and characterization of a novel human pancreas-specific gene, pancpin, that is down-regulated in pancreatic cancer cells.

    Genes Chromosomes Cancer 1998, 22:179-185. PubMed Abstract | Publisher Full Text OpenURL

  50. Carrell RW, Lomas DA: Conformational disease.

    Lancet 1997, 350:134-138. PubMed Abstract | Publisher Full Text OpenURL

  51. Saunders DN, Tindall EA, Shearer RF, Roberson J, Decker A, Wilson JA, Hayes VM: A novel SERPINA1 mutation causing serum alpha(1)-antitrypsin deficiency.

    PLoS One 2012, 7:e51762. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  52. Liu Y, Bledsoe G, Hagiwara M, Shen B, Chao L, Chao J: Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling.

    Am J Physiol Renal Physiol 2012, 303:F1230-F1238. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  53. Jeunemaitre X, Gimenez-Roqueplo AP, Celerier J, Corvol P: Angiotensinogen variants and human hypertension.

    Curr Hypertens Rep 1999, 1:31-41. PubMed Abstract | Publisher Full Text OpenURL

  54. Van de Water N, Tan T, Ashton F, O'Grady A, Day T, Browett P, Ockelford P, Harper P: Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia.

    Br J Haematol 2004, 127:190-194. PubMed Abstract | Publisher Full Text OpenURL

  55. Corral J, Gonzalez-Conejero R, Soria JM, Gonzalez-Porras JR, Perez-Ceballos E, Lecumberri R, Roldan V, Souto JC, Minano A, Hernandez-Espinosa D, Alberca I, Fontcuberta J, Vicente V: A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis.

    Blood 2006, 108:177-183. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  56. Gooptu B, Hazes B, Chang WS, Dafforn TR, Carrell RW, Read RJ, Lomas DA: Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease.

    Proc Natl Acad Sci U S A 2000, 97:67-72. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  57. Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA: Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.

    Endocr Res 2004, 30:417-429. PubMed Abstract | Publisher Full Text OpenURL

  58. Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, Bertin T, Napierala D, Morello R, Gibbs R, White L, Miki R, Cohn DH, Crawford S, Travers R, Glorieux FH, Lee B: Mutations in SERPINF1 cause osteogenesis imperfecta type VI.

    J Bone Miner Res 2011, 26:2798-2803. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  59. Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L: Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets.

    Nature 2008, 451:1076-1081. PubMed Abstract | Publisher Full Text OpenURL

  60. Cao D, Zhang Q, Wu LS, Salaria SN, Winter JW, Hruban RH, Goggins MS, Abbruzzese JL, Maitra A, Ho L: Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases.

    Mod Pathol 2007, 20:570-578. PubMed Abstract | Publisher Full Text OpenURL

  61. Vecchi M, Confalonieri S, Nuciforo P, Vigano MA, Capra M, Bianchi M, Nicosia D, Bianchi F, Galimberti V, Viale G, Palermo G, Riccardi A, Campanini R, Daidone MG, Pierotti MA, Pece S, Di Fiore PP: Breast cancer metastases are molecularly distinct from their primary tumors.

    Oncogene 2008, 27:2148-2158. PubMed Abstract | Publisher Full Text OpenURL

  62. Jing Y, Kovacs K, Kurisetty V, Jiang Z, Tsinoremas N, Merchan JR: Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects.

    Mol Cancer Res 2012, 10:1271-1281. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  63. Klein RM, Bernstein D, Higgins SP, Higgins CE, Higgins PJ: SERPINE1 expression discriminates site-specific metastasis in human melanoma.

    Exp Dermatol 2012, 21:551-554. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  64. 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: Common variation in genes related to innate immunity and risk of adult glioma.

    Cancer Epidemiol Biomarkers Prev 2009, 18:1651-1658. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  65. Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, Shen F, Tang ZY, Wang XW: Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma.

    Clin Cancer Res 2007, 13:1133-1139. PubMed Abstract | Publisher Full Text OpenURL

  66. Paterson MA, Hosking PS, Coughlin PB: Expression of the serpin centerin defines a germinal center phenotype in B-cell lymphomas.

    Am J Clin Pathol 2008, 130:117-126. PubMed Abstract | Publisher Full Text OpenURL

  67. Byrne SM, Aucher A, Alyahya S, Elder M, Olson ST, Davis DM, Ashton-Rickardt PG: Cathepsin B controls the persistence of memory CD8+ T lymphocytes.

    J Immunol 2012, 189:1133-1143. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  68. Safdar H, Cheung KL, Salvatori D, Versteeg HH, Laghmani el H, Wagenaar GT, Reitsma PH, van Vlijmen BJ: Acute and severe coagulopathy in adult mice following silencing of hepatic antithrombin and protein C production.

    Blood 2013, 121:4413-4416. PubMed Abstract | Publisher Full Text OpenURL

  69. Yiannikouris F, Karounos M, Charnigo R, English VL, Rateri DL, Daugherty A, Cassis LA: Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice.

    Am J Physiol Regul Integr Comp Physiol 2012, 302:R244-R251. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  70. Baumann M, Pham CT, Benarafa C: SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G .

    Blood 2013, 121:3900-3907.

    S3901-3906

    PubMed Abstract | Publisher Full Text OpenURL

  71. Zaimidou S, van Baal S, Smith TD, Mitropoulos K, Ljujic M, Radojkovic D, Cotton RG, Patrinos GP: A1ATVar: a relational database of human SERPINA1 gene variants leading to alpha1-antitrypsin deficiency and application of the VariVis software.

    Hum Mutat 2009, 30:308-313. PubMed Abstract | Publisher Full Text OpenURL

  72. Lane DA, Olds RJ, Thein SL: Antithrombin III: summary of first database update.

    Nucleic Acids Res 1994, 22:3556-3559. PubMed Abstract | PubMed Central Full Text OpenURL

  73. Kalmar L, Hegedus T, Farkas H, Nagy M, Tordai A: HAEdb: a novel interactive, locus-specific mutation database for the C1 inhibitor gene.

    Hum Mutat 2005, 25:1-5. PubMed Abstract | Publisher Full Text OpenURL

  74. Sabina J, Tobias W: Augmentation therapy with alpha1-antitrypsin: novel perspectives.

    Cardiovasc Hematol Disord Drug Targets 2013, 13:90-98. PubMed Abstract | Publisher Full Text OpenURL

  75. Bornhorst JA, Greene DN, Ashwood ER, Grenache DG: α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population.

    Chest 2013, 143:1000-1008. PubMed Abstract | Publisher Full Text OpenURL

  76. Brenner AV, Neta G, Sturgis EM, Pfeiffer RM, Hutchinson A, Yeager M, Xu L, Zhou C, Wheeler W, Tucker MA, Chanock SJ, Sigurdson AJ: Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer.

    PLoS One 2013, 8:e57243. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  77. Almawi WY, Al-Shaikh FS, Melemedjian OK, Almawi AW: Protein Z, an anticoagulant protein with expanding role in reproductive biology.

    Reproduction 2013, 146:R73-R80. PubMed Abstract | Publisher Full Text OpenURL

  78. Maruyama K, Morishita E, Karato M, Kadono T, Sekiya A, Goto Y, Sato T, Nomoto H, Omi W, Tsuzura S, Imai H, Asakura H, Ohtake S, Nakao S: Antithrombin deficiency in three Japanese families: one novel and two reported point mutations in the antithrombin gene.

    Thromb Res 2013, 132:e118-e123. PubMed Abstract | Publisher Full Text OpenURL

  79. Hepner M, Karlaftis V: Antithrombin.

    Methods Mol Biol 2013, 992:355-364. PubMed Abstract | Publisher Full Text OpenURL

  80. Bork K, Davis-Lorton M: Overview of hereditary angioedema caused by C1-inhibitor deficiency: assessment and clinical management.

    Eur Ann Allergy Clin Immunol 2013, 45:7-16. PubMed Abstract OpenURL