Serpin

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Serpin (serine protease inhibitor)
Serpin (stressed).png
A serpin (white) with its 'reactive centre loop' (blue) bound to a protease (grey). Once the protease attempts catalysis it will be irreversibly inhibited. ( PDB: 1K9O ​)
Identifiers
SymbolSerpin, SERPIN (root symbol of family)
Pfam PF00079
InterPro IPR000215
PROSITE PDOC00256
SCOP2 1hle / SCOPe / SUPFAM
CDD cd00172
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1m37 A:1-378 1hle B:349-379 1jrr A:1-415

1by7 A:1-415 1ova A:1-385 1uhg A:1-385 1jti B:1-385 1att B:77-433 1nq9 L:76-461 1oyh I:76-461 1e03 L:76-461 1e05 I:76-461 1br8 L:76-461 1r1l L:76-461 1lk6 L:76-461 1ant L:76-461 2beh L:76-461 1dzh L:76-461 1ath A:78-461 1tb6 I:76-461 2ant I:76-461p 1dzg I:76-461 1azx L:76-461 1jvq I:76-461 1sr5 A:76-461 1e04 I:76-461 1xqg A:1-375 1xu8 B:1-375 1wz9 B:1-375 1xqj A:1-375 1c8o A:1-300 1m93 A:1-55 1f0c A:1-305 1k9o I:18-392 1sek :18-369 1atu :45-415 1ezx B:383-415 8api A:43-382 1qmb A:49-376 1iz2 A:43-415 1oo8 A:43-415 1d5s B:378-415 7api A:44-382 1qlp A:43-415 1oph A:43-415 1kct :44-415 2d26 A:43-382 9api B:383-415 1psi :47-415 1hp7 A:43-415 3caa A:50-383 1qmn A:43-420 4caa B:390-420 2ach A:47-383 1as4 A:48-383 1yxa B:42-417 1lq8 F:376-406 2pai B:374-406 1pai B:374-406 1jmo A:119-496 1jmj A:119-496 1oc0 A:25-402 1dvn A:25-402 1b3k D:25-402 1dvm D:25-402 1a7c A:25-402 1c5g A:25-402 1db2 B:26-402 9pai A:25-402 1lj5 A:25-402 1m6q A:138-498 1jjo D:101-361

Contents

1imv A:49-415

Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. [1] [2] The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases (serine protease inhibitors). [3] [4] [5] They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. [6] [7] This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site. [8] [9]

Protease inhibition by serpins controls an array of biological processes, including coagulation and inflammation, and consequently these proteins are the target of medical research. [10] Their unique conformational change also makes them of interest to the structural biology and protein folding research communities. [7] [8] The conformational-change mechanism confers certain advantages, but it also has drawbacks: serpins are vulnerable to mutations that can result in serpinopathies such as protein misfolding and the formation of inactive long-chain polymers. [11] [12] Serpin polymerisation not only reduces the amount of active inhibitor, but also leads to accumulation of the polymers, causing cell death and organ failure. [10]

Although most serpins control proteolytic cascades, some proteins with a serpin structure are not enzyme inhibitors, but instead perform diverse functions such as storage (as in egg white—ovalbumin), transport as in hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperoning (HSP47). [9] The term serpin is used to describe these members as well, despite their non-inhibitory function, since they are evolutionarily related. [1]

History

Protease inhibitory activity in blood plasma was first reported in the late 1800s, [13] but it was not until the 1950s that the serpins antithrombin and alpha 1-antitrypsin were isolated, [14] with the subsequent recognition of their close family homology in 1979. [15] [16] That they belonged to a new protein family became apparent on their further alignment with the non-inhibitory egg-white protein ovalbumin, to give what was initially called the alpha1-antitrypsin-antithrombin III-ovalbumin superfamily of serine proteinase inhibitors, [17] but was subsequently succinctly renamed as the Serpins. [18] The initial characterisation of the new family centred on alpha1-antitrypsin, a serpin present in high concentration in blood plasma, the common genetic disorder of which was shown to cause a predisposition to the lung disease emphysema [19] and to liver cirrhosis. [20] The identification of the S and Z mutations [21] [22] responsible for the genetic deficiency and the subsequent sequence alignments of alpha1-antitrypsin and antithrombin in 1982 led to the recognition of the close homologies of the active sites of the two proteins, [23] [24] centred on a methionine [25] in alpha1-antitrypsin as an inhibitor of tissue elastase and on arginine in antithrombin [26] as an inhibitor of thrombin. [27]

The critical role of the active centre residue in determining the specificity of inhibition of serpins was unequivocally confirmed by the finding that a natural mutation of the active centre methionine  in alpha1-antitrypsin to an arginine, as in antithrombin, resulted in a severe bleeding disorder. [28] This active-centre specificity of inhibition was also evident in the many other families of protease inhibitors [7] but the serpins differed from them in being much larger proteins and also in possessing what was soon apparent as an inherent ability to undergo a change in shape. The nature of this conformational change was revealed with the determination in 1984 of the first crystal structure of a serpin, that of post-cleavage alpha1-antitrypsin. [29] This together with the subsequent solving of the structure of native (uncleaved) ovalbumin [30] indicated that the inhibitory mechanism of the  serpins involved a remarkable conformational shift,  with the movement of the exposed peptide loop containing the reactive site and its incorporation as a middle strand in the main beta-pleated sheet that characterises the serpin molecule. [31] [32] Early evidence of the essential role of this loop movement in the inhibitory mechanism came from the finding that even minor aberrations in the amino acid residues that form the hinge of the movement in antithrombin resulted in thrombotic disease. [31] [33] Ultimate confirmation of the linked displacement of the target protease by this loop movement was provided  in 2000 by the structure of the post-inhibitory complex of alpha1-antitrypsin with trypsin, [6] showing how the displacement results in the deformation and inactivation of the attached protease. Subsequent structural studies have revealed an additional advantage of the conformational mechanism [34] in allowing the subtle modulation of inhibitory activity, as notably seen at tissue level [35] with the functionally diverse serpins in human plasma.

Over 1000 serpins have now been identified, including 36 human proteins, as well as molecules in all kingdoms of life—animals, plants, fungi, bacteria, and archaea—and some viruses. [36] [37] [38] The central feature of all is a tightly conserved framework, which allows the precise alignment of their key structural and functional components based on the template structure of alpha1-antitrypsin. [39] In the 2000s, a systematic nomenclature was introduced in order to categorise members of the serpin superfamily based on their evolutionary relationships. [1] Serpins are therefore the largest and most diverse superfamily of protease inhibitors. [40]

Activity

A protease (grey) bound to a serpin reactive centre loop (RCL, blue). When the protease's catalytic triad (red) cleaves the RCL, it becomes trapped in an inactive conformation. (PDB: 1K9O ) Serpin and protease.png
A protease (grey) bound to a serpin reactive centre loop (RCL, blue). When the protease's catalytic triad (red) cleaves the RCL, it becomes trapped in an inactive conformation. ( PDB: 1K9O ​)

Most serpins are protease inhibitors, targeting extracellular, chymotrypsin-like serine proteases. These proteases possess a nucleophilic serine residue in a catalytic triad in their active site. Examples include thrombin, trypsin, and human neutrophil elastase. [41] Serpins act as irreversible, suicide inhibitors by trapping an intermediate of the protease's catalytic mechanism. [6]

Some serpins inhibit other protease classes, typically cysteine proteases, and are termed "cross-class inhibitors". These enzymes differ from serine proteases in that they use a nucleophilic cysteine residue, rather than a serine, in their active site. [42] Nonetheless, the enzymatic chemistry is similar, and the mechanism of inhibition by serpins is the same for both classes of protease. [43] Examples of cross-class inhibitory serpins include serpin B4 a squamous cell carcinoma antigen 1 (SCCA-1) and the avian serpin myeloid and erythroid nuclear termination stage-specific protein (MENT), which both inhibit papain-like cysteine proteases. [44] [45] [46]

Biological function and localization

Protease inhibition

Approximately two-thirds of human serpins perform extracellular roles, inhibiting proteases in the bloodstream in order to modulate their activities. For example, extracellular serpins regulate the proteolytic cascades central to blood clotting (antithrombin), the inflammatory and immune responses (antitrypsin, antichymotrypsin, and C1-inhibitor) and tissue remodelling (PAI-1). [9] By inhibiting signalling cascade proteases, they can also affect development. [47] [48] The table of human serpins (below) provides examples of the range of functions performed by human serpin, as well as some of the diseases that result from serpin deficiency.

The protease targets of intracellular inhibitory serpins have been difficult to identify, since many of these molecules appear to perform overlapping roles. Further, many human serpins lack precise functional equivalents in model organisms such as the mouse. Nevertheless, an important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell. [49] For example, one of the best-characterised human intracellular serpins is Serpin B9, which inhibits the cytotoxic granule protease granzyme B. In doing so, Serpin B9 may protect against inadvertent release of granzyme B and premature or unwanted activation of cell death pathways. [50]

Some viruses use serpins to disrupt protease functions in their host. The cowpox viral serpin CrmA (cytokine response modifier A) is used in order to avoid inflammatory and apoptotic responses of infected host cells. CrmA increases infectivity by suppressing its host's inflammatory response through inhibition of IL-1 and IL-18 processing by the cysteine protease caspase-1. [51] In eukaryotes, a plant serpin inhibits both metacaspases [52] and a papain-like cysteine protease. [53]

Non-inhibitory roles

Non-inhibitory extracellular serpins also perform a wide array of important roles. Thyroxine-binding globulin and transcortin transport the hormones thyroxine and cortisol, respectively. [54] [55] The non-inhibitory serpin ovalbumin is the most abundant protein in egg white. Its exact function is unknown, but it is thought to be a storage protein for the developing foetus. [56] Heat shock serpin 47 is a chaperone, essential for proper folding of collagen. It acts by stabilising collagen's triple helix whilst it is being processed in the endoplasmic reticulum. [57]

Some serpins are both protease inhibitors and perform additional roles. For example, the nuclear cysteine protease inhibitor MENT, in birds also acts as a chromatin remodelling molecule in a bird's red blood cells. [45] [58]

Structure

The native state of serpins is an equilibrium between a fully stressed state (left) and a partially relaxed state (right). The five-stranded A-sheet (light blue) contains two functionally important regions for the serpin's mechanism, the breach and the shutter. The reactive centre loop (RCL, blue) exists in a dynamic equilibrium between the fully exposed conformation (left) and a conformation where it is partially inserted into the breach of the A-sheet (right).(PDB: 1QLP, 1YXA ) Serpin equilibrium.png
The native state of serpins is an equilibrium between a fully stressed state (left) and a partially relaxed state (right). The five-stranded A-sheet (light blue) contains two functionally important regions for the serpin's mechanism, the breach and the shutter. The reactive centre loop (RCL, blue) exists in a dynamic equilibrium between the fully exposed conformation (left) and a conformation where it is partially inserted into the breach of the A-sheet (right).( PDB: 1QLP, 1YXA ​)

All serpins share a common structure (or fold), despite their varied functions. All typically have three β-sheets (named A, B and C) and eight or nine α-helices (named hA–hI). [29] [30] The most significant regions to serpin function are the A-sheet and the reactive centre loop (RCL). The A-sheet includes two β-strands that are in a parallel orientation with a region between them called the 'shutter', and upper region called the 'breach'. The RCL forms the initial interaction with the target protease in inhibitory molecules. Structures have been solved showing the RCL either fully exposed or partially inserted into the A-sheet, and serpins are thought to be in dynamic equilibrium between these two states. [8] The RCL also only makes temporary interactions with the rest of the structure, and is therefore highly flexible and exposed to the solvent. [8]

The serpin structures that have been determined cover several different conformations, which has been necessary for the understanding of their multiple-step mechanism of action. Structural biology has therefore played a central role in the understanding of serpin function and biology. [8]

Conformational change and inhibitory mechanism

Inhibitory serpins do not inhibit their target proteases by the typical competitive (lock-and-key) mechanism used by most small protease inhibitors (e.g. Kunitz-type inhibitors). Instead, serpins use an unusual conformational change, which disrupts the structure of the protease and prevents it from completing catalysis. The conformational change involves the RCL moving to the opposite end of the protein and inserting into β-sheet A, forming an extra antiparallel β-strand. This converts the serpin from a stressed state, to a lower-energy relaxed state (S to R transition). [7] [8] [61]

Serine and cysteine proteases catalyse peptide bond cleavage by a two-step process. Initially, the catalytic residue of the active site triad performs a nucleophilic attack on the peptide bond of the substrate. This releases the new N-terminus and forms a covalent ester-bond between the enzyme and the substrate. [7] This covalent complex between enzyme and substrate is called an acyl-enzyme intermediate. For standard substrates, the ester bond is hydrolysed and the new C-terminus is released to complete catalysis. However, when a serpin is cleaved by a protease, it rapidly undergoes the S to R transition before the acyl-enzyme intermediate is hydrolysed. [7] The efficiency of inhibition depends on fact that the relative kinetic rate of the conformational change is several orders of magnitude faster than hydrolysis by the protease.

Since the RCL is still covalently attached to the protease via the ester bond, the S to R transition pulls protease from the top to the bottom of the serpin and distorts the catalytic triad. The distorted protease can only hydrolyse the acyl enzyme intermediate extremely slowly and so the protease remains covalently attached for days to weeks. [6] Serpins are classed as irreversible inhibitors and as suicide inhibitors since each serpin protein permanently inactivates a single protease, and can only function once. [7]

Serpin mechanism (S to R).png
The inhibitory mechanism of serpins involves a large conformational change (S to R transition). The serpin (white) first binds a protease (grey) with the exposed reactive centre loop (blue). When this loop is cleaved by the protease, it rapidly inserts into the A-sheet (light blue), deforming and inhibiting the protease. ( PDB: 1K9O, 1EZX ​)
Serpin mechanism.png
Serine and cysteine proteases operate by a two-step catalytic mechanism. First, the substrate (blue) is attacked by the cysteine or serine of the catalytic triad (red) to form an acyl-enzyme intermediate. For typical substrates, the intermediate is resolved by hydrolysis by water. However, when the reactive centre loop (RCL) of a serpin is attacked, the conformational change (blue arrow) pulls the catalytic triad out of position, preventing it from completing catalysis. (Based on PDB: 1K9O, 1EZX ​)

Allosteric activation

Some serpins are activated by cofactors. The serpin antithrombin has an RCL (blue) where the P1 arginine (blue sticks) points inwards, preventing protease binding. Binding of heparin (green sticks) causes the P1 arginine residue to flip to an exposed position. The target protease (grey) then binds to both the exposed P1 arginine as well as the heparin. The serpin then activates and heparin is released. (PDB: 1TB6, 2ANT, 1TB6, 1EZX ) Serpin activation by heparin (unannotated).png
Some serpins are activated by cofactors. The serpin antithrombin has an RCL (blue) where the P1 arginine (blue sticks) points inwards, preventing protease binding. Binding of heparin (green sticks) causes the P1 arginine residue to flip to an exposed position. The target protease (grey) then binds to both the exposed P1 arginine as well as the heparin. The serpin then activates and heparin is released. ( PDB: 1TB6, 2ANT, 1TB6, 1EZX ​)

The conformational mobility of serpins provides a key advantage over static lock-and-key protease inhibitors. [34] In particular, the function of inhibitory serpins can be regulated by allosteric interactions with specific cofactors. The X-ray crystal structures of antithrombin, heparin cofactor II, MENT and murine antichymotrypsin reveal that these serpins adopt a conformation wherein the first two amino acids of the RCL are inserted into the top of the A β-sheet. The partially inserted conformation is important because co-factors are able to conformationally switch certain partially inserted serpins into a fully expelled form. [62] [63] This conformational rearrangement makes the serpin a more effective inhibitor.

The archetypal example of this situation is antithrombin, which circulates in plasma in a partially inserted relatively inactive state. The primary specificity determining residue (the P1 arginine) points toward the body of the serpin and is unavailable to the protease. Upon binding a high-affinity pentasaccharide sequence within long-chain heparin, antithrombin undergoes a conformational change, RCL expulsion, and exposure of the P1 arginine. The heparin pentasaccharide-bound form of antithrombin is, thus, a more effective inhibitor of thrombin and factor Xa. [64] [65] Furthermore, both of these coagulation proteases also contain binding sites (called exosites) for heparin. Heparin, therefore, also acts as a template for binding of both protease and serpin, further dramatically accelerating the interaction between the two parties. After the initial interaction, the final serpin complex is formed and the heparin moiety is released. This interaction is physiologically important. For example, after injury to the blood vessel wall, heparin is exposed, and antithrombin is activated to control the clotting response. Understanding of the molecular basis of this interaction enabled the development of Fondaparinux, a synthetic form of Heparin pentasaccharide used as an anti-clotting drug. [66] [67]

Latent conformation

Some serpins can spontaneously convert to an inactive latent state. The serpin PAI-1 remains in the active conformation when bound to vitronectin (green). However, in the absence of vitronectin, PAI-1 can change to the inactive latent state. The uncleaved RCL (blue; disordered regions as dashed lines) inserts into the A-sheet, pulling a b-strand off the C-sheet (yellow). (PDB: 1OC0, 1DVM, 1LJ5 ) Serpin latent state (unannotated).png
Some serpins can spontaneously convert to an inactive latent state. The serpin PAI-1 remains in the active conformation when bound to vitronectin (green). However, in the absence of vitronectin, PAI-1 can change to the inactive latent state. The uncleaved RCL (blue; disordered regions as dashed lines) inserts into the A-sheet, pulling a β-strand off the C-sheet (yellow). ( PDB: 1OC0, 1DVM, 1LJ5 ​)

Certain serpins spontaneously undergo the S to R transition without having been cleaved by a protease, to form a conformation termed the latent state. Latent serpins are unable to interact with proteases and so are no longer protease inhibitors. The conformational change to latency is not exactly the same as the S to R transition of a cleaved serpin. Since the RCL is still intact, the first strand of the C-sheet has to peel off to allow full RCL insertion. [68]

Regulation of the latency transition can act as a control mechanism in some serpins, such as PAI-1. Although PAI-1 is produced in the inhibitory S conformation, it "auto-inactivates" by changing to the latent state unless it is bound to the cofactor vitronectin. [68] Similarly, antithrombin can also spontaneously convert to the latent state, as an additional modulation mechanism to its allosteric activation by heparin. [69] Finally, the N-terminus of tengpin, a serpin from Thermoanaerobacter tengcongensis , is required to lock the molecule in the native inhibitory state. Disruption of interactions made by the N-terminal region results in spontaneous conformational change of this serpin to the latent conformation. [70] [71]

Conformational change in non-inhibitory functions

Certain non-inhibitory serpins also use the serpin conformational change as part of their function. For example, the native (S) form of thyroxine-binding globulin has high affinity for thyroxine, whereas the cleaved (R) form has low affinity. Similarly, transcortin has higher affinity for cortisol when in its native (S) state, than its cleaved (R) state. Thus, in these serpins, RCL cleavage and the S to R transition has been commandeered to allow for ligand release, rather than protease inhibition. [54] [55] [72]

In some serpins, the S to R transition can activate cell signalling events. In these cases, a serpin that has formed a complex with its target protease, is then recognised by a receptor. The binding event then leads to downstream signalling by the receptor. [73] The S to R transition is therefore used to alert cells to the presence of protease activity. [73] This differs from the usual mechanism whereby serpins affect signalling simply by inhibiting proteases involved in a signalling cascade. [47] [48]

Degradation

When a serpin inhibits a target protease, it forms a permanent complex, which needs to be disposed of. For extracellular serpins, the final serpin-enzyme complexes are rapidly cleared from circulation. One mechanism by which this occurs in mammals is via the low-density lipoprotein receptor-related protein (LRP), which binds to inhibitory complexes made by antithrombin, PA1-1, and neuroserpin, causing cellular uptake. [73] [74] Similarly, the Drosophila serpin, necrotic, is degraded in the lysosome after being trafficked into the cell by the Lipophorin Receptor-1 (homologous to the mammalian LDL receptor family). [75]

Disease and serpinopathies

Serpins are involved in a wide array of physiological functions, and so mutations in genes encoding them can cause a range of diseases. Mutations that change the activity, specificity or aggregation properties of serpins all affect how they function. The majority of serpin-related diseases are the result of serpin polymerisation into aggregates, though several other types of disease-linked mutations also occur. [8] [76] The disorder alpha-1 antitrypsin deficiency is one of the most common hereditary diseases. [11] [77]

Inactivity or absence

The inactive d-conformation of the disease-linked antichymotrypsin mutant (L55P). Four residues of the RCL (blue; disordered region as dashed line) are inserted into the top of the A-sheet. Part of the F a-helix (yellow) has unwound and fills the bottom half of the A-sheet. (PDB: 1QMN ) Serpin delta conformation.png
The inactive δ-conformation of the disease-linked antichymotrypsin mutant (L55P). Four residues of the RCL (blue; disordered region as dashed line) are inserted into the top of the A-sheet. Part of the F α-helix (yellow) has unwound and fills the bottom half of the A-sheet. ( PDB: 1QMN ​)

Since the stressed serpin fold is high-energy, mutations can cause them to incorrectly change into their lower-energy conformations (e.g. relaxed or latent) before they have correctly performed their inhibitory role. [10]

Mutations that affect the rate or the extent of RCL insertion into the A-sheet can cause the serpin to undergo its S to R conformational change before having engaged a protease. Since a serpin can only make this conformational change once, the resulting misfired serpin is inactive and unable to properly control its target protease. [10] [78] Similarly, mutations that promote inappropriate transition to the monomeric latent state cause disease by reducing the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants wibble and wobble, [79] both promote formation of the latent state.

The structure of the disease-linked mutant of antichymotrypsin (L55P) revealed another, inactive "δ-conformation". In the δ-conformation, four residues of the RCL are inserted into the top of β-sheet A. The bottom half of the sheet is filled as a result of one of the α-helices (the F-helix) partially switching to a β-strand conformation, completing the β-sheet hydrogen bonding. [80] It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role, but it is speculated that the δ-conformation may be adopted by Thyroxine-binding globulin during thyroxine release. [55] The non-inhibitory proteins related to serpins can also cause diseases when mutated. For example, mutations in SERPINF1 cause osteogenesis imperfecta type VI in humans. [81]

In the absence of a required serpin, the protease that it normally would regulate is over-active, leading to pathologies. [10] Consequently, simple deficiency of a serpin (e.g. a null mutation) can result in disease. [82] Gene knockouts, particularly in mice, are used experimentally to determine the normal functions of serpins by the effect of their absence. [83]

Specificity change

In some rare cases, a single amino acid change in a serpin's RCL alters its specificity to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (M358R) causes the α1-antitrypsin serpin to inhibit thrombin, causing a bleeding disorder. [28]

Polymerisation and aggregation

Serpin polymerisation by domain swapping
Domainswappeddimer.png
A domain-swapped serpin dimer. ( PDB: 2ZNH ​)
Antitrypsindomswap.png
A domain-swapped serpin trimer. Each monomer's RCL is inserted into its own structure (shown in red of the green monomer). ( PDB: 3T1P ​)

The majority of serpin diseases are due to protein aggregation and are termed "serpinopathies". [12] [80] Serpins are vulnerable to disease-causing mutations that promote formation of misfolded polymers due to their inherently unstable structures. [80] Well-characterised serpinopathies include α1-antitrypsin deficiency (alpha-1), which may cause familial emphysema, and sometimes liver cirrhosis, certain familial forms of thrombosis related to antithrombin deficiency, types 1 and 2 hereditary angioedema (HAE) related to deficiency of C1-inhibitor, and familial encephalopathy with neuroserpin inclusion bodies (FENIB; a rare type of dementia caused by neuroserpin polymerisation). [11] [12] [84]

Each monomer of the serpin aggregate exists in the inactive, relaxed conformation (with the RCL inserted into the A-sheet). The polymers are therefore hyperstable to temperature and unable to inhibit proteases. Serpinopathies therefore cause pathologies similarly to other proteopathies (e.g. prion diseases) via two main mechanisms. [11] [12] First, the lack of active serpin results in uncontrolled protease activity and tissue destruction. Second, the hyperstable polymers themselves clog up the endoplasmic reticulum of cells that synthesize serpins, eventually resulting in cell death and tissue damage. In the case of antitrypsin deficiency, antitrypsin polymers cause the death of liver cells, sometimes resulting in liver damage and cirrhosis. Within the cell, serpin polymers are slowly removed via degradation in the endoplasmic reticulum. [85] However, the details of how serpin polymers cause cell death remains to be fully understood. [11]

Physiological serpin polymers are thought to form via domain swapping events, where a segment of one serpin protein inserts into another. [86] Domain-swaps occur when mutations or environmental factors interfere with the final stages of serpin folding to the native state, causing high-energy intermediates to misfold. [87] Both dimer and trimer domain-swap structures have been solved. In the dimer (of antithrombin), the RCL and part of the A-sheet incorporates into the A-sheet of another serpin molecule. [86] The domain-swapped trimer (of antitrypsin) forms via the exchange of an entirely different region of the structure, the B-sheet (with each molecule's RCL inserted into its own A-sheet). [88] It has also been proposed that serpins may form domain-swaps by inserting the RCL of one protein into the A-sheet of another (A-sheet polymerisation). [84] [89] These domain-swapped dimer and trimer structures are thought to be the building blocks of the disease-causing polymer aggregates, but the exact mechanism is still unclear. [86] [87] [88] [90]

Therapeutic strategies

Several therapeutic approaches are in use or under investigation to treat the most common serpinopathy: antitrypsin deficiency. [11] Antitrypsin augmentation therapy is approved for severe antitrypsin deficiency-related emphysema. [91] In this therapy, antitrypsin is purified from the plasma of blood donors and administered intravenously (first marketed as Prolastin). [11] [92] To treat severe antitrypsin deficiency-related disease, lung and liver transplantation has proven effective. [11] [93] In animal models, gene targeting in induced pluripotent stem cells has been successfully used to correct an antitrypsin polymerisation defect and to restore the ability of the mammalian liver to secrete active antitrypsin. [94] Small molecules have also been developed that block antitrypsin polymerisation in vitro. [95] [96]

Evolution

Serpins are the most widely distributed and largest superfamily of protease inhibitors. [1] [40] They were initially believed to be restricted to eukaryote organisms, but have since been found in bacteria, archaea and some viruses. [36] [37] [97] It remains unclear whether prokaryote genes are the descendants of an ancestral prokaryotic serpin or the product of horizontal gene transfer from eukaryotes. Most intracellular serpins belong to a single phylogenetic clade, whether they come from plants or animals, indicating that the intracellular and extracellular serpins may have diverged before the plants and animals. [98] Exceptions include the intracellular heat shock serpin HSP47, which is a chaperone essential for proper folding of collagen, and cycles between the cis-Golgi and the endoplasmic reticulum. [57]

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. [55]

Distribution

Animal

Human

The human genome encodes 16 serpin clades, termed serpinA through serpinP, including 29 inhibitory and 7 non-inhibitory serpin proteins. [9] [83] 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. [1] [36] [83] The functions of human serpins have been determined by a combination of biochemical studies, human genetic disorders, and knockout mouse models. [83]

Table of human serpins
Gene nameCommon NameLocalisationFunction / Activity [9] [83] Effect of deficiency [9] [83] Human diseaseChromosomal locationProtein structure
SERPINA1 α1-antitrypsin ExtracellularInhibitor of human neutrophil elastase. [99] The C-terminal fragment of cleaved SERPINA1 may inhibit HIV-1 infection. [100] Deficiency results in emphysema, polymerisation results in cirrhosis (serpinopathy). [11] [101] 14q32.1 1QLP ​, 7API ​, 1D5S ​
SERPINA2 Antitrypsin-related protein ExtracellularPossible pseudogene. [102] 14q32.1
SERPINA3 α1-antichymotrypsin ExtracellularInhibitor of cathepsin G. [103] Additional roles in chromatin condensation in hepatic cells. [104] Mis-regulation results in Alzheimer's disease (serpinopathy). [105] 14q32.1 1YXA ​, 2ACH ​
SERPINA4 Kallistatin ExtracellularInhibitor of kallikrein, regulator of vascular function. [106] [107] Depletion in hypertensive rats exacerbates renal and cardiovascular injury. [108] 14q32.1
SERPINA5 Protein C inhibitor ExtracellularInhibitor of active protein C. [109] Intracellular role in preventing phagocytosis of bacteria. [110] Knockout in male mice causes infertility. [111] Accumulation occurs in chronic active plaques in multiple sclerosis. [112] 14q32.1 2OL2 ​, 3B9F ​
SERPINA6 Transcortin ExtracellularNon-inhibitory. Cortisol binding. [54] Deficiency associated with chronic fatigue. [113] 14q32.1 2V6D ​, 2VDX ​, 2VDY ​
SERPINA7 Thyroxine-binding globulin ExtracellularNon-inhibitory. Thyroxine binding. [55] Deficiency causes hypothyroidism. [114] [115] Xq22.2 2CEO ​, 2RIV ​, 2RIW ​
SERPINA8 Angiotensinogen ExtracellularNon-inhibitory, cleavage by renin results in release of angiotensin I. [116] Knockout in mice causes hypotension. [117] Variants linked to hypertension. [118] [119] [120] 1q42-q43 2X0B ​, 2WXW ​, 2WXX ​, 2WXY ​, 2WXZ ​, 2WY0 ​, 2WY1 ​
SERPINA9 Centerin / GCET1ExtracellularInhibitory, maintenance of naive B cells. [121] [122] Strongly expressed in most B-cell lymphomas. [123] [124] 14q32.1
SERPINA10 Protein Z-related protease inhibitor ExtracellularBinds protein Z and inactivates factor Xa and factor XIa. [125] 14q32.1 3F1S ​, 3H5C ​
SERPINA11 –Probably extracellularUnknown14q32.13
SERPINA12 Vaspin ExtracellularInhibitor of Kallikrein-7. Insulin-sensitizing adipocytokine. [126] High plasma levels associated with type II diabetes. [127] 14q32.1 4IF8 ​
SERPINA13 –Probably extracellularUnknown14q32
SERPINB1 Monocyte neutrophil elastase inhibitor IntracellularInhibitor of neutrophil elastase. [128] Knockout in mice causes neutrophil survival defect and immune deficiency. [129] 6p25 1HLE ​
SERPINB2 Plasminogen activator inhibitor-2 Intracellular/extracellularInhibitor of extracellular uPA. Intracellular function unclear, but may protect against viral infection. [130] Deficiency in mice reduces immune response to nematode infection. [131] Knockout in mice causes no obvious phenotype. [132] 18q21.3 1BY7 ​
SERPINB3 Squamous cell carcinoma antigen-1 (SCCA-1)IntracellularInhibitor of papain-like cysteine proteases [44] and cathepsins K, L and S. [133] [134] Knockout in mice of Serpinb3a (the murine homolog of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma. [135] 18q21.3 2ZV6 ​
SERPINB4 Squamous cell carcinoma antigen-2 (SCCA-2)IntracellularInhibitor of chymotrypsin-like serine proteases, cathepsin G and chymase. [134] [136] Knockout in mice of Serpinb3a (the murine homolog of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma. [135] 18q21.3
SERPINB5 Maspin IntracellularNon-inhibitory, function unclear [137] [138] [139] (see also maspin)Knockout in mice originally reported as lethal, [140] but subsequently shown to have no obvious phenotype. [139] Expression may be a prognostic indicator that reflects expression of a neighbouring tumour suppressor gene (the phosphatase PHLPP1). [139] 18q21.3 1WZ9 ​
SERPINB6 PI-6 IntracellularInhibitor of cathepsin G. [141] Knockout in mice causes hearing loss [142] and mild neutropenia. [143] Deficiency associated with hearing loss. [144] 6p25
SERPINB7 Megsin IntracellularInvolved in megakaryocyte maturation. [145] Over-expression in mice causes kidney disease. [146] Knockout in mice does not cause histological abnormalities. [146] Mutations associated with Nagashima-type Palmoplantar Keratosis. [147] 18q21.3
SERPINB8 PI-8 IntracellularPossible inhibitor of furin. [148] 18q21.3
SERPINB9 PI-9 IntracellularInhibitor of the cytotoxic granule protease granzyme B. [149] Knockout in mice causes immune dysfunction. [150] [151] 6p25
SERPINB10 Bomapin IntracellularUnknown [152] Knockout in mice causes no obvious phenotype (C57/BL6; lab strain BC069938).18q21.3
SERPINB11 IntracellularUnknown [153] Murine Serpinb11 is an active inhibitor whereas the human orthalogue is inactive. [153] Deficiency in ponies is associated with hoof wall separation disease. [154] 18q21.3
SERPINB12 Yukopin IntracellularUnknown [155] 18q21.3
SERPINB13 Hurpin/Headpin IntracellularInhibitor of papain-like cysteine proteases. [156] 18q21.3
SERPINC1 Antithrombin ExtracellularInhibitor of coagulation, specifically factor X, factor IX and thrombin. [34] Knockouts in mice are lethal. [157] Deficiency results in thrombosis and other clotting disorders (serpinopathy). [158] [159] 1q23-q21 2ANT ​, 2ZNH ​, 1AZX ​, 1TB6 ​, 2GD4 ​, 1T1F ​
SERPIND1 Heparin cofactor II ExtracellularInhibitor of thrombin. [160] Knockouts in mice are lethal. [161] 22q11 1JMJ ​, 1JMO ​
SERPINE1 Plasminogen activator inhibitor 1 ExtracellularInhibitor of thrombin, uPA and TPa. [162] 7q21.3-q22 1DVN ​, 1OC0 ​
SERPINE2 Glia derived nexin / Protease nexin I ExtracellularInhibitor of uPA and tPA. [163] Abnormal expression leads to male infertility. [164] Knockout in mice causes epilepsy. [165] 2q33-q35 4DY0 ​
SERPINF1 Pigment epithelium derived factor ExtracellularNon-inhibitory, potent anti-angiogenic molecule. [166] PEDF has been reported to bind the glycosaminoglycan hyaluronan. [167] Knockout in mice affects the vasculature and mass of the pancreas and the prostate. [166] Promotes Notch–dependent renewal of adult periventricular neural stem cells. [168] Mutations in humans cause osteogenesis imperfecta type VI. [81] 17p13.3 1IMV ​
SERPINF2 α2-antiplasmin ExtracellularInhibitor of plasmin, inhibitor of fibrinolysis. [169] Knockouts in mice show increased mice show increased fibrinolysis but no bleeding disorder. [170] Deficiency causes a rare bleeding disorder. [171] [172] 17pter-p12 2R9Y ​
SERPING1 Complement 1-inhibitor ExtracellularInhibitor of C1 esterase. [173] Several polymorphisms associated with macular degeneration [174] and hereditary angeoedema. [175] 11q11-q13.1 2OAY ​
SERPINH1 47 kDa Heat shock protein (HSP47)IntracellularNon-inhibitory, molecular chaperone in collagen folding. [57] Knockouts in mice are lethal. [176] Mutation in humans causes severe osteogenesis imperfecta. [177] [178] 11p15 4AXY ​
SERPINI1 Neuroserpin ExtracellularInhibitor of tPA, uPA and plasmin. [179] Mutation causes FENIB dementia (serpinopathy). [180] [181] 3q26 1JJO ​, 3FGQ ​, 3F5N ​, 3F02 ​
SERPINI2 Pancpin ExtracellularUnknown [182] Deficiency in mice causes pancreatic insufficiency via acinar cell loss. [183] 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. [184] 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. [185]

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. [186] 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). [186] [187] [188]

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. [48] [189] [190] In Tenebrio molitor (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade. [191]

Nematode

The genome of the nematode worm C. elegans contains 9 serpins, all of which lack signal sequences and so are likely intracellular. [192] However, only 5 of these serpins appear to function as protease inhibitors. [192] 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. [193]

Plant

Plant serpins were amongst the first members of the superfamily that were identified. [194] 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. [195] 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. [196] [197] 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) [198] and cucumber plants. [199] [200] 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. [198]

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. [53] [201] AtSerpin1 also inhibits metacaspase-like proteases in vitro. [52] Two other Arabidopsis serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage. [202]

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. [38] It is therefore suggested that celpin may protect the cellulosome against plant proteases. Certain bacterial serpins similarly localize to the cellulosome. [203]

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. [204] [205] 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. [203]

Viral

Serpins are also expressed by viruses as a way to evade the host's immune defense. [206] 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. [207] [208] Serp1 suppresses the TLR-mediated innate immune response and allows indefinite cardiac allograft survival in rats. [207] [209] Crma and Serp2 are both cross-class inhibitors and target both serine (granzyme B; albeit weakly) and cysteine proteases (caspase 1 and caspase 8). [210] [211] 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. [212]

Related Research Articles

<span class="mw-page-title-main">Alpha-1 antitrypsin</span> Mammalian protein found in Homo sapiens

Alpha-1 antitrypsin or α1-antitrypsin is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases. In older biomedical literature it was sometimes called serum trypsin inhibitor, because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L, but the concentration can rise manyfold upon acute inflammation.

<span class="mw-page-title-main">Antithrombin</span> Mammalian protein found in Homo sapiens

Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

<span class="mw-page-title-main">Alpha 2-antiplasmin</span> Protein-coding gene in the species Homo sapiens

Alpha 2-antiplasmin is a serine protease inhibitor (serpin) responsible for inactivating plasmin. Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.

<span class="mw-page-title-main">Ovalbumin</span> Main protein found in egg white

Ovalbumin is the main protein found in egg white, making up approximately 55% of the total protein. Ovalbumin displays sequence and three-dimensional homology to the serpin superfamily, but unlike most serpins it is not a serine protease inhibitor. The function of ovalbumin is unknown, although it is presumed to be a storage protein.

<span class="mw-page-title-main">Factor X</span> Mammalian protein found in Homo sapiens

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme of the coagulation cascade. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

<span class="mw-page-title-main">Plasminogen activator</span> Type of protein

Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotting. There are two main plasminogen activators: urokinase (uPA) and tissue plasminogen activator (tPA). Tissue plasminogen activators are used to treat medical conditions related to blood clotting including embolic or thrombotic stroke, myocardial infarction, and pulmonary embolism.

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

<span class="mw-page-title-main">Heparin cofactor II</span> Protein-coding gene in the species Homo sapiens

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

<span class="mw-page-title-main">Plasminogen activator inhibitor-2</span> Coagulation factor protein found in humans

Plasminogen activator inhibitor-2, a serine protease inhibitor of the serpin superfamily, is a coagulation factor that inactivates tissue plasminogen activator and urokinase. It is present in most cells, especially monocytes/macrophages. PAI-2 exists in two forms, a 60-kDa extracellular glycosylated form and a 43-kDa intracellular form.

<span class="mw-page-title-main">Alpha 1-antichymotrypsin</span> Protein-coding gene in the species Homo sapiens

Alpha 1-antichymotrypsin is an alpha globulin glycoprotein that is a member of the serpin superfamily. In humans, it is encoded by the SERPINA3 gene.

<span class="mw-page-title-main">Protein C inhibitor</span> Human protein

Protein C inhibitor is a serine protease inhibitor (serpin) that limits the activity of protein C.

<span class="mw-page-title-main">Maspin</span> Protein-coding gene in the species Homo sapiens

Maspin is a protein that in humans is encoded by the SERPINB5 gene. This protein belongs to the serpin superfamily. SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues. Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis. However, a subsequent study using viral transduction as a method of gene transfer was not able to reproduce the original findings and found no role for maspin in tumour biology. Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype. These data are consistent with the observation that maspin is not expressed in early embryogenesis. The precise molecular function of maspin is thus currently unknown.

<span class="mw-page-title-main">SERPINB9</span> Protein-coding gene in the species Homo sapiens

Serpin B9 is a protein that in humans is encoded by the SERPINB9 gene. PI9 belongs to the large superfamily of serine proteinase inhibitors (serpins), which bind to and inactivate serine proteinases. These interactions are involved in many cellular processes, including coagulation, fibrinolysis, complement fixation, matrix remodeling, and apoptosis .[supplied by OMIM]

<span class="mw-page-title-main">SERPINB6</span> Protein-coding gene in the species Homo sapiens

Serpin B6 is a protein that in humans is encoded by the SERPINB6 gene.

<span class="mw-page-title-main">SERPINB1</span> Protein-coding gene in the species Homo sapiens

Leukocyte elastase inhibitor (LEI) also known as serpin B1 is a protein that in humans is encoded by the SERPINB1 gene. It is a member of the clade B serpins or ov-serpins founded by ovalbumin.

<span class="mw-page-title-main">SERPINB8</span> Protein-coding gene in the species Homo sapiens

Serpin B8 is a protein that in humans is encoded by the SERPINB8 gene.

<span class="mw-page-title-main">SERPINA2</span> Protein-coding gene in the species Homo sapiens

Serpin peptidase inhibitor, clade A, member 2 is a protein that in humans is encoded by the SERPINA2 gene. Serine peptidase inhibitor, clade A member 2 belongs to the member of serine family of proteins which have a functional activity of inhibiting serine proteases.

<span class="mw-page-title-main">SERPINB10</span> Protein-coding gene in the species Homo sapiens

Serpin peptidase inhibitor, clade B (ovalbumin), member 10 is a protein that in humans is encoded by the SERPINB10 gene.

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