SERPINA2

Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), 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.[3]

SERPINA2
Identifiers
Aliases	SERPINA2, ARGS, ATR, PIL, SERPINA2P, psiATR, serpin family A member 2 (gene/pseudogene)
External IDs	GeneCards: SERPINA2
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q32.13 Start 94,364,313 bp[1] End 94,366,698 bp[1]
Gene ontology Molecular function • peptidase inhibitor activity • GO:0001948 protein binding • serine-type endopeptidase inhibitor activity Cellular component • endoplasmic reticulum • extracellular Biological process • negative regulation of peptidase activity • negative regulation of endopeptidase activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	390502	n/a
Ensembl	ENSG00000274821 ENSG00000258597	n/a
UniProt	P20848	n/a
RefSeq (mRNA)	NM_006220	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	Chr 14: 94.36 – 94.37 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Discovery

SERPINA2 was known as pseudogenes as it had a very similar structure and function to SERPINA1. During the cloning characterisation of alpha 1- antitrypsin like gene, it was discovered that SERPINA2 did not have any promoter but did contain substantial homology to SERPINA1 gene sequence.[4]

Gene location

SERPINA2 is located at 14q32.13.[5]

Gene expression and localisation

Extracellular predictions of SERPINs and common domain clades show that ER localisation of SERPINA2 are most likely be more, these common ER motifs indicates their localisation are most likely to be in the ER.[6]

Structure

Population studies indicate that this gene is polymorphic. Deletions, frameshift mutations, and a critical start codon mutation (ATG to ATA) have been found in some populations, as well as an allele that can encode a functional protein. This gene may be an evolving pseudogene.[7] The reference genome contains the start codon mutation and has a coding region deletion. A three-dimensional model of SERPINA2 was created using the non-deleted form of crystal structure, which is homologous with the SERPINA1 protein. The model was created using swissmodel in EXPASY, and has shown that SERPINA2 preserves a SERPIN reactive centre loop which is most compatible with protease inhibitory activity. The consensus sequence surrounding the reactive centre loop have diverged considerably so that now it contains tryptophan sarin motifs instead of the methionine serine motif.[8]

Function

SERPINA2 was previously identified as pseudogene; however, recently there have been new evidence which specifies that SERPINA2 produces an active transcript that is responsible for encoding protein located in the endoplasmic reticulum. A detailed study of the SERPINA2 gene across multiple ethnic groups have relieved that with the addition of SERPINA2 gene therein a haplotype characterisation by partial deletion which has patterns suggesting positive selection of loss of function of SERPINA2 protein.[5]

SERPINA2 studies have shown different results regarding the extent of sequence degeneration it can undergo.[7] Bao et al. (1988) describes in his studies that sequence with RNA splice sites are preserved in SERPINA2, and when expressed, it encodes a new secretory protein (SERPIN) with different substrate specificity. These studies with SERPINA2 in humans have concluded that recent positive selection is favoured by the loss of SERPINA2 function and pseudogenization.[9] SERPINA2 genes are mostly expressed in leukocytes and testes which gives a residual expression in liver. SERPINA2 have been linked with on going adaptive process linked with advantages in the role of fertility and host pathogen interactions.[8]

Mutations

A critical mutation present in the start codon and an 2kb deletion over exon IV and part of exon V. This deletion in the start codon occurs at a frequency of 30%.[4] Studies with SERPINA2 in vitro and in vivo have shown that it expresses stable proteins with n-linked glycosylation with a molecular weight of 52kDa and compatible with regular SERPINs [8]

Disease associated

SERPINA2 is a member of SERPIN family, which are known as protein coding genes. A disease associated with this gene is emphysema, due to aat protein deficiency. SERPINA2 has similar function to SERPINA1 and is related to the function of serine type peptidase inhibitor activity.[10]

References

1. ENSG00000258597 GRCh38: Ensembl release 89: ENSG00000274821, ENSG00000258597 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Entrez Gene: Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2". Retrieved 2017-09-21.
4. Hofker MH, Nelen M, Klasen EC, Nukiwa T, Curiel D, Crystal RG, Frants RR (September 1988). "Cloning and characterization of an alpha 1-antitrypsin like gene 12 KB downstream of the genuine alpha 1-antitrypsin gene". Biochemical and Biophysical Research Communications. 155 (2): 634–42. doi:10.1016/S0006-291X(88)80542-4. PMID 2901833.
5. Heit C, Jackson BC, McAndrews M, Wright MW, Thompson DC, Silverman GA, Nebert DW, Vasiliou V (October 2013). "Update of the human and mouse SERPIN gene superfamily". Human Genomics. 7 (1): 22. doi:10.1186/1479-7364-7-22. PMC 3880077. PMID 24172014.
6. Marques PI, Ferreira Z, Martins M, Figueiredo J, Silva DI, Castro P, Morales-Hojas R, Simões-Correia J, Seixas S (June 2013). "SERPINA2 is a novel gene with a divergent function from SERPINA1". PLOS ONE. 8 (6): e66889. doi:10.1371/journal.pone.0066889. PMC 3691238. PMID 23826168.
7. Seixas S, Suriano G, Carvalho F, Seruca R, Rocha J, Di Rienzo A (February 2007). "Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2". Molecular Biology and Evolution. 24 (2): 587–98. doi:10.1093/molbev/msl187. PMID 17135331.
8. Marques PI, Ferreira Z, Martins M, Figueiredo J, Silva DI, Castro P, Morales-Hojas R, Simões-Correia J, Seixas S (June 2013). "SERPINA2 is a novel gene with a divergent function from SERPINA1". PLOS ONE. 8 (6): e66889. doi:10.1371/journal.pone.0066889. PMC 3691238. PMID 23826168.
9. Bao JJ, Reed-Fourquet L, Sifers RN, Kidd VJ, Woo SL (February 1988). "Molecular structure and sequence homology of a gene related to alpha 1-antitrypsin in the human genome". Genomics. 2 (2): 165–73. doi:10.1016/0888-7543(88)90099-7. PMID 2842251.
10. "SERPINA2". GeneCards.

Further reading

• Merkel, PA; Xie, G; Monach, PA; Ji, X; Ciavatta, DJ (May 2017). "Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis". Arthritis & Rheumatology. 69 (5): 1054-66. doi:10.1002/art.40034. PMC 5434905. PMID 28029757.
• Namciu SJ, Friedman RD, Marsden MD, Sarausad LM, Jasoni CL, Fournier RE (March 2004). "Sequence organization and matrix attachment regions of the human serine protease inhibitor gene cluster at 14q32.1". Mammalian Genome. 15 (3): 162–78. doi:10.1007/s00335-003-2311-y. PMID 15014966.
• Rollini P, Fournier RE (December 1997). "Molecular linkage of the human alpha 1-antitrypsin and corticosteroid-binding globulin genes on chromosome 14q32.1". Mammalian Genome. 8 (12): 913–6. doi:10.1007/s003359900610. PMID 9383284.
• Gettins PG, Olson ST (August 2016). "Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance". Biochemical Journal. 473 (15): 2273–2293. doi:10.1042/bcj20160014. PMC 5266585. PMID 27470592.