Uterine serpin

Last updated
Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 14
Identifiers
Organism Bos taurus (domestic cow)
SymbolSERPINA14
Entrez 286871
RefSeq (mRNA) NM_174797
RefSeq (Prot) NP_777222
UniProt P46201
Other data
Chromosome 21: 59.39 - 59.4 Mb
Search for
Structures Swiss-model
Domains InterPro

Uterine serpins are members of the A clade of the serine protease inhibitor (serpin) superfamily of proteins and are encoded by the SERPINA14 gene. Uterine serpins are produced by the endometrium of a restricted group of mammals under the influence of progesterone or estrogen. These proteins appear to be inactive protease inhibitors and may function during pregnancy to regulate immune function or participate in transplacental transport.

Contents

Nomenclature

Uterine serpins were originally described in the uterine secretions of unilaterally-pregnant sheep as a pair of 57 kDa and 55 kDa glycoproteins. [1] Termed uterine milk proteins, their identification as members of the serpin superfamily was based on sequencing of the cDNA for the sheep gene. [2] The pig uterine serpin was first identified because of its association with an iron-binding uterine protein termed uteroferrin. [3] [4] and was originally termed uteroferrin-associated protein. [5]

The designation of uterine serpins as SERPINA14 [6] is based on their classification as a highly-divergent group of the α1-antitrypsin or A clade. [7] In other analyses, uterine serpins have been considered as a separate clade in the serpin superfamily. [8]

Evolution

The uterine serpins are novel with respect to other serpins by virtue of their limited distribution among mammals. They have been described only in species of the Laurasiatheria superorder of eutherian mammals. Among the clades in which uterine serpin genes exist are the Cetartiodactyla (dolphin, cow, water buffalo, sheep, goat, pig), Perissodactyla (horse) and some carnivores (dog, giant panda) [6] [9] The uterine serpin gene is not expressed in all carnivores since the only uterine serpin identified in the cat is a pseudogene. [6] Examination of completed genomes indicates that uterine serpin genes do not exist in primates, mouse, rat, rabbit, marsupials, platypus, chicken or zebrafish. [6] [10]

Figure 1. Immunohistochemical localization of uterine serpin in endometrial glands of an ovariectomized ewe treated with progesterone for 60 days. Uterine serpin localized to endometrial glands in the sheep uterus.jpg
Figure 1. Immunohistochemical localization of uterine serpin in endometrial glands of an ovariectomized ewe treated with progesterone for 60 days.

Cellular expression and hormone regulation

Uterine serpins are products of the endometrial epithelium (Figure 1). Gene expression is limited to epithelial cells of endometrial glands. [11] Late in pregnancy, uterine serpin protein can be found in the lumenal epithelium as well, [12] perhaps as glandular epithelial cells move to the uterine lumen.

The major regulator of uterine serpin gene expression is progesterone. [6] In the cow, estrogen can also increase uterine serpin gene expression. [13] [14]

In addition to expression in the endometrium, bovine uterine serpin is also expressed in the ovary (follicles, corpus luteum, and cumulus-oocyte complex) and by cotyledons of the placenta. [14] [15]

Protease inhibitory activity

There are two lines of evidence to indicate that uterine serpins do not function as protease inhibitors. Uterine serpins from the sheep and pig are not inhibitory towards a variety of proteases. [2] [5] [16] [17] In addition, several key amino acids in the hinge region of the reactive center loop which are important for protease inhibitory activity have not been conserved in uterine serpins. [6] Bovine uterine serpin does inhibit pepsin but probably through a mechanism distinct from the prototypical mechanism used by serpins. [17]

Function during pregnancy

There are two possible biological roles for uterine serpins during pregnancy. The first is as a binding protein. Porcine uterine serpin binds non-covalently to uteroferrin in a way that stabilizes the iron-binding capacity of uteroferrin. [4] Uteroferrin is transferred across the placenta where it gives up its iron to fetal transferrin. [18] Ovine uterine serpin binds pregnancy-associated glycoproteins, [17] which are inactive aspartic proteases secreted in large amounts by the ungulate placenta. [19] Ovine uterine serpin also binds to activin, [20] IgM and IgA. [21]

Another possible role for uterine serpins is in the inhibition of immune cell proliferation during pregnancy to provide protection for the allogeneically-distinct conceptus. In particular, sheep uterine serpin can inhibit lymphocyte and natural killer cell function in vitro and reduce natural-killer cell mediated abortion in a mouse model. [22]

Genetics

A single nucleotide polymorphism at position 1269 of the bovine uterine serpin gene has been associated with productive life [23] in cattle populations. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Endometrium</span> Inner mucous membrane of the mammalian uterus

The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer thickens and then is shed during menstruation in humans and some other mammals, including apes, Old World monkeys, some species of bat, the elephant shrew and the Cairo spiny mouse. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.

<span class="mw-page-title-main">Transcortin</span> Protein found in humans

Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin.

<span class="mw-page-title-main">Serpin</span> Superfamily of proteins with similar structures and diverse functions

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. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. 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. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.

Interferon tau is a Type I interferon made of a single chain of amino acids. IFN-τ was first discovered in ruminants as the signal for the maternal recognition of pregnancy and originally named ovine trophoblast protein-1 (oTP-1). It has many physiological functions in the mammalian uterus, and also has anti-inflammatory effect that aids in the protection of the semi-allogeneic conceptus trophectoderm from the maternal immune system.

<i>Jaagsiekte sheep retrovirus</i> Species of virus

Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.

<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">Implantation (embryology)</span> First stage of pregnancy

Implantation, also known as nidation is the stage in the embryonic development of mammals in which the blastocyst hatches, attaches, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. In a woman, an implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.

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

Glycodelin(GD) also known as human placental protein-14 (PP-14)progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential role in the pregnancy process. In humans is encoded by the PAEP gene.

<span class="mw-page-title-main">MMP26</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase-26 also known as matrilysin-2 and endometase is an enzyme that in humans is encoded by the MMP26 gene.

<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">KLF9</span> Protein-coding gene in the species Homo sapiens

Krueppel-like factor 9 is a protein that in humans is encoded by the KLF9 gene. Previously known as Basic Transcription Element Binding Protein 1, Klf9 is part of the Sp1 C2H2-type zinc finger family of transcription factors. Several previous studies showed Klf9-related regulation of animal development, including cell differentiation of B cells, keratinocytes, and neurons. Klf9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are turned off during tumorigenesis.

<span class="mw-page-title-main">SERPINA9</span> Protein-coding gene in the species Homo sapiens

Serpin A9 also known as centerin or GCET1 is a protein that in humans is encoded by the SERPINA9 gene located on chromosome 14q32.1. Serpin A9 is a member of the serpin family of serine protease inhibitors.

<span class="mw-page-title-main">MMP27</span> Protein-coding gene in the species Homo sapiens

Matrix metallopeptidase 27 also known as MMP-27 is an enzyme which in humans is encoded by the MMP27 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">Retinol-binding protein</span> Family of proteins that bind retinol

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.

B13R is a protein expressed by vaccinia virus.

<span class="mw-page-title-main">Maternal recognition of pregnancy</span> Crucial aspect of carrying a pregnancy to full term

Maternal recognition of pregnancy is a crucial aspect of carrying a pregnancy to full term. Without maternal recognition to maintain pregnancy, the initial messengers which stop luteolysis and promote foetal implantation, growth and uterine development finish with nothing to replace them and the pregnancy is lost.

SERPIN A12

Serpin A12 is a glycoprotein that is a class A member of the serine protease inhibitor (serpin) family. In humans, Serpin A12 is encoded by the SERPINA12 gene.

References

  1. ↑ Moffatt J, Bazer FW, Hansen PJ, Chun PW, Roberts RM (March 1987). "Purification, secretion and immunocytochemical localization of the uterine milk proteins, major progesterone-induced proteins in uterine secretions of the sheep". Biol. Reprod. 36 (2): 419–30. doi: 10.1095/biolreprod36.2.419 . PMID   3580461.
  2. 1 2 Ing NH, Roberts RM (February 1989). "The major progesterone-modulated proteins secreted into the sheep uterus are members of the serpin superfamily of serine protease inhibitors". J. Biol. Chem. 264 (6): 3372–9. doi: 10.1016/S0021-9258(18)94076-7 . PMID   2464597.
  3. ↑ Ibelgaufts H (2002-01-01). "Uteroferrin". Cytokines & Cells Encyclopedia - COPE. Retrieved 2010-12-02.
  4. 1 2 Baumbach GA, Ketcham CM, Richardson DE, Bazer FW, Roberts RM (September 1986). "Isolation and characterization of a high molecular weight stable pink form of uteroferrin from uterine secretions and allantoic fluid of pigs". J. Biol. Chem. 261 (27): 12869–78. doi: 10.1016/S0021-9258(18)67173-X . PMID   3017991.
  5. 1 2 Malathy PV, Imakawa K, Simmen RC, Roberts RM (March 1990). "Molecular cloning of the uteroferrin-associated protein, a major progesterone-induced serpin secreted by the porcine uterus, and the expression of its mRNA during pregnancy". Mol. Endocrinol. 4 (3): 428–40. doi: 10.1210/mend-4-3-428 . PMID   2342477.
  6. 1 2 3 4 5 6 Padua MB, Kowalski AA, Cañas MY, Hansen PJ (February 2010). "The molecular phylogeny of uterine serpins and its relationship to evolution of placentation". FASEB J. 24 (2): 526–37. doi:10.1096/fj.09-138453. PMID   19825977. S2CID   9248169.
  7. ↑ Irving JA, Pike RN, Lesk AM, Whisstock JC (December 2000). "Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function". Genome Res. 10 (12): 1845–64. doi: 10.1101/gr.GR-1478R . PMID   11116082.
  8. ↑ Peltier MR, Raley LC, Liberles DA, Benner SA, Hansen PJ (August 2000). "Evolutionary history of the uterine serpins". J. Exp. Zool. 288 (2): 165–74. doi:10.1002/1097-010X(20000815)288:2<165::AID-JEZ7>3.0.CO;2-R. PMID   10931499.
  9. ↑ Padua MB, Hansen PJ (October 2010). "Evolution and function of the uterine serpins (SERPINA14)". Am. J. Reprod. Immunol. 64 (4): 265–74. doi: 10.1111/j.1600-0897.2010.00901.x . PMID   20678169.
  10. ↑ van Gent D, Sharp P, Morgan K, Kalsheker N (November 2003). "Serpins: structure, function and molecular evolution". Int. J. Biochem. Cell Biol. 35 (11): 1536–47. doi:10.1016/S1357-2725(03)00134-1. PMID   12824063.
  11. ↑ Stewart MD, Johnson GA, Gray CA, et al. (June 2000). "Prolactin receptor and uterine milk protein expression in the ovine endometrium during the estrous cycle and pregnancy". Biol. Reprod. 62 (6): 1779–89. doi: 10.1095/biolreprod62.6.1779 . PMID   10819783.
  12. ↑ Stephenson DC, Leslie MV, Low BG, Newton GR, Hansen PJ, Bazer FW (October 1989). "Secretion of the major progesterone-induced proteins of the sheep uterus by caruncular and intercaruncular endometrium of the pregnant ewe from days 20-140 of gestation". Domest. Anim. Endocrinol. 6 (4): 349–62. doi:10.1016/0739-7240(89)90029-5. PMID   2620505.
  13. ↑ Bauersachs S, Ulbrich SE, Gross K, et al. (June 2005). "Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes". J. Mol. Endocrinol. 34 (3): 889–908. doi: 10.1677/jme.1.01799 . PMID   15956356.
  14. 1 2 Ulbrich SE, Frohlich T, Schulke K, et al. (October 2009). "Evidence for estrogen-dependent uterine serpin (SERPINA14) expression during estrus in the bovine endometrial glandular epithelium and lumen". Biol. Reprod. 81 (4): 795–805. doi: 10.1095/biolreprod.108.075184 . PMID   19494250.
  15. 1 2 Khatib H, Schutzkus V, Chang YM, Rosa GJ (May 2007). "Pattern of expression of the uterine milk protein gene and its association with productive life in dairy cattle". J. Dairy Sci. 90 (5): 2427–33. doi: 10.3168/jds.2006-722 . PMID   17430947.
  16. ↑ Liu WJ, Hansen PJ (February 1995). "Progesterone-induced secretion of dipeptidyl peptidase-IV (cluster differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation". Endocrinology. 136 (2): 779–87. doi:10.1210/endo.136.2.7835310. PMID   7835310.
  17. 1 2 3 Mathialagan N, Hansen TR (November 1996). "Pepsin-inhibitory activity of the uterine serpins". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 13653–8. Bibcode:1996PNAS...9313653M. doi: 10.1073/pnas.93.24.13653 . PMC   19381 . PMID   8942989.
  18. ↑ Buhi WC, Ducsay CA, Bazer FW, Roberts RM (February 1982). "Iron transfer between the purple phosphatase uteroferrin and transferrin and its possible role in iron metabolism of the fetal pig". J. Biol. Chem. 257 (4): 1712–23. doi: 10.1016/S0021-9258(19)68096-8 . PMID   7056739.
  19. ↑ Green JA, Xie S, Roberts RM (January 1998). "Pepsin-related molecules secreted by trophoblast". Rev. Reprod. 3 (1): 62–9. doi:10.1530/ror.0.0030062. PMID   9509990.
  20. ↑ McFarlane JR, Foulds LM, O'Connor AE, et al. (October 1999). "Uterine milk protein, a novel activin-binding protein, is present in ovine allantoic fluid". Endocrinology. 140 (10): 4745–52. doi: 10.1210/en.140.10.4745 . PMID   10499534.
  21. ↑ Hansen PJ, Newton GR (January 1988). "Binding of immunoglobulins to the major progesterone-induced proteins secreted by the sheep uterus". Arch. Biochem. Biophys. 260 (1): 208–17. doi:10.1016/0003-9861(88)90442-0. PMID   3341741.
  22. ↑ Hansen PJ (October 1998). "Regulation of uterine immune function by progesterone--lessons from the sheep". J. Reprod. Immunol. 40 (1): 63–79. doi:10.1016/S0165-0378(98)00035-7. PMID   9862257.
  23. ↑ Schutz M. "Using Net Merit To Select Dairy Bulls". Purdue University. Retrieved 2010-12-02.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.