HSP47: Family Members

Hsp47 is a member of the SERPIN superfamily of proteinase inhibitors. The SERPIN superfamily comprises the most common proteinase inhibitors and can be found in all five kingdoms of life 20. SERPIN family members are encoded by a multigene family comprising 35 putatively functional protein-coding genes and six pseudogenes in humans, with many of the genes found in two clusters on chromosomes 14 (most clade A serpins) and 18 (clade B serpins), reflecting the role of gene duplication and differentiation in their familial expansion (Table 2). Serpins are classified into clades due to their sequence similarity and phylogenetic relationship. 16 Clades have been defined (termed A–P), with 9 clades (A–I) covering human serpins (Table 2). The two largest clades of serpins identified so far are the extracellular ‘clade A’ members and the intracellular ‘clade B’ serpins.

Clade A comprises three pseudogenes (SERPINA7P1, SERPINA13P, SERPINA15P) as well as 12 functional genes, encoding extracellular serpins that are characterized as being anti-trypsin-like. Serpin A1, also termed α1-antitrypsin or α1-protease inhibitor (α1-PI), is an inhibitory molecule crucially involved in the blockage of neutrophil elastase 39. SERPINA2 was originally described as a pseudogene, but new lines of evidence indicate it is a functional gene coding for ER-resident Serpin A2 with putative serine proteinase activity 40.  Serpin A3, also termed α1-antichymotrypsin, represents an inflammatory response molecule with inhibitory function. Although its physiological function remains unsolved, Serpin A3 is capable of blocking neutrophil cathepsin G and mast cell chymase, both of which are able to convert inactive angiotensin-1 to the active angiotensin-2 41. Serpin A4 and Serpin A5 are further inhibitory serpins. While Serpin A4 acts as a kallikrein inhibitor 42, Serpin A5 functions as a pro-coagulant and pro-inflammatory agent by blocking the activation of the anti-coagulant, protein C factor 43, 44. Serpin A5 also functions as an anti-coagulant by blocking blood coagulation factors and fibrinolytic enzymes including urokinase (uPA) 45, reflecting the ambivalent nature of this serpin. Clade A serpins also encompass the non-inhibitory hormone-transport molecules Serpin A6 (corticosteroid-binding globulin, CNP) and Serpin A7 (thyroxine-binding globulin). While Serpin A6 has been shown to bind to hormones (e.g. glucocorticoids) 46, Serpin A7 represents the main thyroid hormone transport protein in serum 47. Serpin A8 (angiotensinogen, AGT) is an indispensable component of the renin-angiotensin system (RAS), and functions as a strong regulator of blood pressure, body fluid and electrolyte homeostasis 48, 49. Serpin A9 (centerin) represents a serine proteinase inhibitor highly expressed in normal germinal center (GC) B-cells and GC B-cell-derived malignancies, playing a pivotal role in naïve B cell maintenance 50. Serpin A10 is expressed in the liver and secreted into the plasma. Serpin A10 triggers blood coagulation as it inhibits the coagulation protease factor Xa in the presence of protein Z and factor XIa in the absence of co-factors 51. Serpin A10 has an N-terminal extension which is relevant for adjuvant functions and responsible for a fundamental increase of its molecular mass 52. Serpin A11 was originally characterized as being a pseudogene. Nowadays it has become apparent that Serpin A11 acts as a serpin proteinase inhibitor highly expressed in liver 53. Serpin A12 (vaspin) is expressed in visceral adipose tissues and functions as an adipokine which modulates insulin sensitivity by blocking its target protease, kallikrein-7 54.

Clade B encompasses intracellular serpins that are crucially involved in inflammatory processes 55, mucous production 56, and regulating immune responses 57-59. Ubiquitously expressed Serpin B1 (leukocyte elastase inhibitor, LEI) is a regulator of neutrophil proteases including cathepsin G, chymase, chymotrypsin, elastase, proteinase-3, and kallikrein-3 and acts as a potent granzyme H inhibitor 60. Serpin B2, plasminogen activator inhibitor (PAI-2), represents a urokinase (uPA) inhibitor which plays a prominent role in fibrinolysis 61. The squamous cell-specific Serpin B3 and Serpin B4 are closely related proteinase inhibitors that modulate the host’s immune response against tumor cells 62, 63. The corresponding genes are regularly co-expressed in the same tissues, including bladder, blood, esophagus, lung, heart, prostate, testis, thymus, and trachea, and uterus, with the exception of SERPINB4 which could not be identified in bladder and thymus 64. The non-inhibitory Serpin B5 (maspin) functions as a tumor suppressor in normal mammary epithelial cells. Interestingly, Serpin B5 does not undergo the characteristic serpin-like conformational change found in active serpins 65. The ubiquitously expressed Serpin B6 represents a cathepsin G inhibitor known to block inappropriate activity of cytotoxic apoptotic proteases 66. Serpin B6 has been proposed to protect the inner ear against leakage of lysosomal content during stress. Failure of this protection leads to cell death and sensorineural hearing loss 67. Serpin B7 (megsin) is preferentially expressed in mesangial cells where it regulates the cell proliferation and secretion of collagen type IV 68. Serpin B9, also known as peptidase inhibitor 9 (PI-9), acts as a specific inhibitor of granzyme B and plays a crucial role in mediating immune responses 69, 70. Inhibitory Serpin B10 (bomapin) holds a key role in regulating protease activities during TNF-mediated hematopoiesis and apoptosis 71, 72. Serpin B10 is expressed specifically in myeloid cells and the bone marrow 72. Serpin B11 does not harbor any protease inhibitory activity, possibly due to single nucleotide polymorphisms encoding amino acid variants in the serpin scaffold that impede conformational re-arrangements 73. It is obviously expressed in a limited number of tissues only, including lung, placenta, prostate, and tonsil 73. Serpin B12 (yukopin) acts as a trypsin and plasmin inhibitor, but not as an inhibitor of thrombin 74. The serpin was detected in several tissues, including brain, bone marrow, heart, intestine, lymph node, lung, liver, pancreas, testis, and ovary 74. Finally, Serpin B13 (headpin, hurpin) represents a cysteine endopeptidase inhibitor which exerts regulatory activities in keratinocyte development 75.

Clade C and Clade D contain a single serpin only. Serpin C1 (also named antithrombin, antithrombin-III) represents a crucial serine proteinase inhibitor in plasma which regulates the blood coagulation cascade. Serpin C1 was found to block thrombin, matriptase-3/TMPRSS7 as well as the coagulation factors IXa, Xa and XIa 76. Serpin D1 (heparin cofactor II) can be found in the plasma and predominantly in liver where it acts as a prominent thrombin and chymotrypsin inhibitor 77. Serpin D1 has been demonstrated to utilize co-factor recruitment and conformational transition to achieve striking inhibitory activity 78. Serpin C1 and Serpin D1 bear sizable N-terminal extensions supposed to mediate adjuvant functions of the molecules 52.

Clade E encompasses three extracellular serpins. Serpin E1 (plasminogen activator inhibitor 1, PAI-1) is the primary inhibitor of tissue- (tPA) and urokinase-type plasminogen activators (uPA), enzymes that convert plasminogen to plasmin, leading to fibrin degradation. Serpin E1, one of the main anti-fibrinolytic proteins, has been found to block thrombin and matriptase-3/TMPRSS7 76, 79. It is predominantly expressed in endothelial cells and can be found not only in plasma, but also in platelets as well as in hepatoma and fibrosarcoma cells 80, 81. Serpin E2, also named Glia-derived nexin (GDN), is an extracellular serine proteinase inhibitor known to inhibit several proteases including thrombin 82. GDN has been shown to affect the kinetics of re-innervation and the recovery of sensory and motor functions after peripheral nerve injury 83. It is ubiquitiously expressed with highest expression levels found in decidua. The poorly characterized Serpin E3 (nexin-related serine proteinase inhibitor) represents a putative extracellular serine proteinase inhibitor which is highly expressed in liver. Two isoforms have been identified for this molecule as the result of alternative splicing yielding proteins 424 and 404 amino acid residues in length, respectively.

Clade F contains two extracellular serpins. Serpin F1 (pigment epithelium-derived factor, PEDF) has been noted to act as a neurotrophic factor which induces extensive neuronal differentiation 84. As Serpin F1 does not exhibit the well characterized conformational change of active serpins, it lacks any serine proteinase inhibitory activity 85. Moreover, this serpin serves as a potent inhibitor of angiogenesis 86. Serpin F1 is ubiquitiously expressed with high expression levels found in the pigmented layer of retina. Serpin F2, also termed α2-antiplasmin (α2-AP), represents a strong inhibitor of fibrinolysis as it targets plasmin and trypsin, but it also blocks matriptase-3/TMPRSS7 and chymotrypsin 76. Serpin F2 is predominantly expressed in the liver and secreted into the plasma. Two isoforms have been identified for this molecule as the result of alternative splicing yielding proteins 491 and 427 amino acid residues in length, respectively.

In clade G and clade H, only a single serpin each is present. Serpin G1 (plasma protease C1 inhibitor) serves as a serine proteinase inhibitor which is active against complement C1s and C1r, kallikrein as well as factor XII 87. It is broadly expressed with highest levels found in the liver. Serpin G1 bears an N-terminal extension of approximately 100 amino acid resues which is highly glycosylated, thereby increasing the molecular mass of the circulating protein to ~104 kDa 88. The non-inhibitory Serpin H1, also termed Hsp47, is an ER-resident unique molecular chaperone crucially involved in the correct folding of procollagen 2, 3. Serpin H1, whose expression is induced by cell stress including heat shock 15, can be found in a broad spectrum of tissues with highest expression levels found in smooth muscle tissue. An autosomal-recessive missense mutation in the SERPINH1 gene coding for Hsp47 has been identified to cause a severe phenotype of osteogenesis imperfecta 89.

Clade I comprises two extracellular serpins. Serpin I1, also known as neuroserpin, acts as a serine proteinase inhibitor which blocks tissue- and urokinase-type plasminogen activators (tPA, uPA) as well as plasmin, but not thrombin 90. Serpin I1 is widely expressed with highest levels found in the brain 91 and has been proposed to play a pivotal role in the organization of synaptic connections as well as for synaptic plasticity in the adult nervous system 92. Noteworthy, Serpin I1 containing an S49P mutation has been characterized to cause a new form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB) 93. A significant correlation was drawn between Serpin I1 expression and adult glioma by Rajaraman and colleagues 94. Serpin I2 (pancpin), which is predominantly expressed in pancreas and adipose tissues 95, exhibits serine proteinase inhibitory activity against pancreatic elastase and chymotrypsin 96. Serpin I2 is down-regulated in pancreatic and breast cancer, and associated with acinar cell apoptosis and pancreatic insufficiency 95, 96.

Table 2a: The clade A of the human Serpin superfamily of proteinase inhibitors

Protein UniProt ID Aliases Length (aa) Chromosome Gene ID
Clade A
Serpin A1 P01009 α1-antitrypsin, α1-protease inhibitor (α1-PI) 418, 359, 306 14q32.13 5265
Serpin A2 P20848 putative α1-antitrypsin-related protein 420 14q32.13 390502
Serpin A3 P01011 α1-antichymotrypsin, cell growth-inhibiting gene 24/25 protein 423, 216, 95 14q32.13 12
Serpin A4 P29622 Kallistatin, kallikrein inhibitor, peptidase inhibitor 4 427 14q32.13 5267
Serpin A5 P05154 Plasma serine protease inhibitor, plasminogen activator inhibitor 3 (PAI-3), protein C inhibitor (PCI) 406 14q32.13 5104
Serpin A6 P08185 Corticosteroid-binding globulin (CBP), transcortin 405 14q32.13 866
Serpin A7 P05543 Thyroxin-binding globulin, T4-binding globulin 415 Xq22.3 6906
Serpin A7P1   Pseudogene Xq22.3 100422644
Serpin A8 P01019 Angiotensinogen (AGT) 485 1q42.2 183
Serpin A9 Q86WD7 Centerin, germinal center B-cell-expressed transcript 1 protein (GCET1), serine proteinase inhibitor A11 417, 335, 201, 334, 286, 337, 435 14q32.13 327657
Serpin A10 Q9UK55 Protein Z-dependent protease inhibitor (PZI) 444 14q32.13 51156
Serpin A11 Q86U17 Antiproteinase-like 2 422 14q32.13 256394
Serpin A12 Q8IW75 OL-64, visceral adipose tissue-derived serine protease inhibitor (vaspin) 414 14q32.13 145264
Serpin A13P Pseudogene 14q32.13 388007
Serpin A15P Pseudogene 8q23.3 101930744


Table 2b: The clade B of the human Serpin superfamily of proteinase inhibhitors

Protein UniProt ID Aliases Length (aa) Chromosome Gene ID
Clade B
Serpin B1 P30740 leukocyte elastase inhibitor (LEI), monocyte/neutrophil elastase inhibitor (EI), peptidase inhibitor 2 (PI-2), epididymis luminal protein 57, epididymis secretory protein Li 27 379, 228 6p25.2 1992
Serpin B2 P05120 Plasminogen activator inhibitor (PAI-2), urokinase inhibitor, placental plasminogen activator inhibitor 415 18q21.33-q22.1 5055
Serpin B3 P29508 Protein T4-A, squamous cell carcinoma antigen 1 (SCCA-1) 390, 338 18q21.33 6317
Serpin B4 P48594 Leupin, peptidase inhibitor 11 (PI-11), squamous cell carcinoma antigen 2 (SCCA-2) 390 18q21.33 6318
Serpin B5 P36952 Maspin, peptidase inhibitor 5 (PI-5) 375, 231 18q21.33 5268
Serpin B6 P35237 Cytoplasmic antiproteinase (CAP), peptidase inhibitor 6 (PI-6), placental thrombin inhibitor 376 6p25.2 5269
Serpin B7 O75635 Megsin, TP55 380, 363 18q21.33 8710
Serpin B8P1   Pseudogene 6p25.2 11029
Serpin B9 P50453 Cytoplasmic antiproteinase 3 (CAP-3), peptidase inhibitor 9 (PI-9), testicular tissue protein Li 180 376 6p25.2 5272
Serpin B9P1   Pseudogene 6p25.2 221756
Serpin B10 P48595 Bomapin, peptidase inhibitor 10 (PI-10) 397 18q22.1 5273
Serpin B11 Q96P15 Serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 11 392, 305, 190 18q21.33 89778
Serpin B12 Q96P63 Yukopin, serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 12 405, 425 18q21.33 89777
Serpin B13 Q9UIV8 Headpin, HaCaT UV-repressible serpin (hurpin), UV-B repressed sequence (HUR7), peptidase inhibitor 13 (PI-13) 391, 339 18q21.33 5275


Table 2c: The clades C – I of the human Serpin superfamily of proteinase inhibhitors

Protein UniProt ID Aliases Length (aa) Chromosome Gene ID
Clade C
Serpin C1 P01008 Antithrombin-III (ATIII), serpin peptidase inhibitor clade C member 1, antithrombin 464 1q25.1 462
Clade D
Serpin D1 P05546 Heparin cofactor 2,  HC-II, protease inhibitor leuserpin-2 (HLS-2) 499 22q11.21


Clade E
Serpin E1 P05121 Plasminogen activator inhibitor 1 (PAI-1), endothelial plasminogen activator inhibitor 402, 387 7q22.1 5054
Serpin E2 P07093 Glia-derived nexin (GDN), peptidase inhibitor 7 (PI-7), protease nexin 1 (PN-1) 398, 397, 409 2q36.1 5270
Serpin E3 A8MV23 Nexin-related serine protease inhibitor; serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 3 424, 404 13q14.3 647174
Clade F
Serpin F1 P36955 Pigment epithelium-derived factor (PEDF), EPC-1, cell proliferation-inducing gene 35 protein, testis tissue sperm-binding protein Li 70n  418 17p13.3 5176
Serpin F2 P08697 α2-antiplasmin (α2-AP), α2-plasmin inhibitor (α2-PI) 491, 427 17p13.3 5345
Clade G
Serpin G1 P05155 Plasma protease C1 inhibitor (C1Inh), C1 esterase inhibitor, C1-inhibiting factor, complement component 1 inhibitor, epididymis secretory sperm binding protein 500, 448, 505 11q12.1 710
Clade H
Serpin H1 P50454 47 kDa heat shock protein (Hsp47), arsenic-transactivated protein 3 (AsTP3), cell proliferation-inducing gene 14 protein, collagen-binding protein 1/-2 (CBP-1/-2), colligin-1/-2, rheumatoid arthritis-related antigen RA-A47, gp46, J6 418 11q13.5 871
Serpin H1P1 Pseudogene 9p13.3 158172
Clade I
Serpin I1 Q99574 Neuroserpin, peptidase inhibitor 12 (PI-12), serpin peptidase inhibitor clade I member 1 410 3q26.1 5274
Serpin I2 O75830 Pancpin, myoepithelium-derived serine protease inhibitor, pancreas-specific protein TSA2004, peptidase inhibitor 14 (PI-14), serpin peptidase inhibitor clade I  member 2 405 3q26.1 5276