SPA12_HUMAN
ID SPA12_HUMAN Reviewed; 414 AA.
AC Q8IW75;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Serpin A12;
DE AltName: Full=OL-64;
DE AltName: Full=Visceral adipose tissue-derived serine protease inhibitor;
DE Short=Vaspin;
DE AltName: Full=Visceral adipose-specific serpin;
DE Flags: Precursor;
GN Name=SERPINA12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16030142; DOI=10.1073/pnas.0504703102;
RA Hida K., Wada J., Eguchi J., Zhang H., Baba M., Seida A., Hashimoto I.,
RA Okada T., Yasuhara A., Nakatsuka A., Shikata K., Hourai S., Futami J.,
RA Watanabe E., Matsuki Y., Hiramatsu R., Akagi S., Makino H., Kanwar Y.S.;
RT "Visceral adipose tissue-derived serine protease inhibitor: a unique
RT insulin-sensitizing adipocytokine in obesity.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:10610-10615(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RA Chen S., Guo J.H., Yu L.;
RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, GLYCOSYLATION AT
RP ASN-221; ASN-233 AND ASN-267, AND MUTAGENESIS OF ASN-221; ASN-233 AND
RP ASN-267.
RX PubMed=28668641; DOI=10.1016/j.bbapap.2017.06.020;
RA Oertwig K., Ulbricht D., Hanke S., Pippel J., Bellmann-Sickert K.,
RA Straeter N., Heiker J.T.;
RT "Glycosylation of human vaspin (SERPINA12) and its impact on serpin
RT activity, heparin binding and thermal stability.";
RL Biochim. Biophys. Acta 1865:1188-1194(2017).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 22-414, FUNCTION, DOMAIN,
RP MUTAGENESIS OF THR-365 AND ALA-369, AND SUBUNIT.
RX PubMed=23370777; DOI=10.1007/s00018-013-1258-8;
RA Heiker J.T., Kloting N., Kovacs P., Kuettner E.B., Strater N., Schultz S.,
RA Kern M., Stumvoll M., Bluher M., Beck-Sickinger A.G.;
RT "Vaspin inhibits kallikrein 7 by serpin mechanism.";
RL Cell. Mol. Life Sci. 70:2569-2583(2013).
RN [6] {ECO:0007744|PDB:4Y3K, ECO:0007744|PDB:4Y40}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 22-414 OF MUTANTS CYS-305;
RP ALA-379 AND CYS-383, FUNCTION, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, DOMAIN, AND MUTAGENESIS OF ARG-302; ASP-305; GLU-379 AND
RP VAL-383.
RX PubMed=26199422; DOI=10.1042/bj20150643;
RA Ulbricht D., Pippel J., Schultz S., Meier R., Strater N., Heiker J.T.;
RT "A unique serpin P1' glutamate and a conserved beta-sheet C arginine are
RT key residues for activity, protease recognition and stability of serpinA12
RT (vaspin).";
RL Biochem. J. 470:357-367(2015).
RN [7] {ECO:0007744|PDB:5EI0}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 22-414, BIOPHYSICOCHEMICAL
RP PROPERTIES, DOMAIN, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF THR-365 AND
RP ALA-369.
RX PubMed=26529565; DOI=10.1515/hsz-2015-0229;
RA Pippel J., Kuettner E.B., Ulbricht D., Daberger J., Schultz S.,
RA Heiker J.T., Strater N.;
RT "Crystal structure of cleaved vaspin (serpinA12).";
RL Biol. Chem. 397:111-123(2016).
RN [8]
RP VARIANT GLY-219.
RX PubMed=27693231; DOI=10.1016/j.ajhg.2016.08.020;
RA Parry D.A., Smith C.E., El-Sayed W., Poulter J.A., Shore R.C., Logan C.V.,
RA Mogi C., Sato K., Okajima F., Harada A., Zhang H., Koruyucu M., Seymen F.,
RA Hu J.C., Simmer J.P., Ahmed M., Jafri H., Johnson C.A., Inglehearn C.F.,
RA Mighell A.J.;
RT "Mutations in the pH-sensing G-protein-coupled receptor GPR68 cause
RT amelogenesis imperfecta.";
RL Am. J. Hum. Genet. 99:984-990(2016).
CC -!- FUNCTION: Adipokine that modulates insulin action by specifically
CC inhibiting its target protease KLK7 in white adipose tissues.
CC {ECO:0000269|PubMed:16030142, ECO:0000269|PubMed:23370777,
CC ECO:0000269|PubMed:26199422, ECO:0000269|PubMed:28668641}.
CC -!- ACTIVITY REGULATION: Inhibition of KLK7 is enhanced by heparin.
CC {ECO:0000269|PubMed:26199422, ECO:0000269|PubMed:28668641}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Temperature dependence:
CC Highly thermostable, with a Tm value of 70 degrees Celsius.
CC Incubation at 60 degrees Celsius for two hours has no apparent effect
CC on KLK7 inhibition activity. Polymerization is observed at 70 degrees
CC Celsius and above. {ECO:0000269|PubMed:26199422,
CC ECO:0000269|PubMed:26529565};
CC -!- SUBUNIT: Forms a stable complex with KLK7.
CC {ECO:0000269|PubMed:23370777}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:28668641}.
CC -!- TISSUE SPECIFICITY: Expressed in visceral adipose tissues.
CC {ECO:0000269|PubMed:16030142}.
CC -!- DOMAIN: The reactive center loop (RCL) extends out from the body of the
CC protein and directs binding to the target protease. The protease
CC cleaves the serpin at the reactive site within the RCL, establishing a
CC covalent linkage between the carboxyl group of the serpin reactive site
CC and the serine hydroxyl of the protease. The resulting inactive serpin-
CC protease complex is highly stable. {ECO:0000305|PubMed:23370777,
CC ECO:0000305|PubMed:26199422, ECO:0000305|PubMed:26529565}.
CC -!- PTM: Glycosylation slightly decreases affinity for heparin, but
CC otherwise has no significant effect on KLK7 inhibitory activity or
CC thermal stability of the protein. {ECO:0000269|PubMed:28668641}.
CC -!- SIMILARITY: Belongs to the serpin family. {ECO:0000305}.
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DR EMBL; AY326420; AAP88384.1; -; mRNA.
DR EMBL; AY177692; AAO18649.1; -; mRNA.
DR EMBL; BC040857; AAH40857.1; -; mRNA.
DR CCDS; CCDS9926.1; -.
DR RefSeq; NP_001291390.1; NM_001304461.1.
DR RefSeq; NP_776249.1; NM_173850.3.
DR RefSeq; XP_011534753.1; XM_011536451.2.
DR RefSeq; XP_011534754.1; XM_011536452.2.
DR RefSeq; XP_011534755.1; XM_011536453.2.
DR RefSeq; XP_011534756.1; XM_011536454.2.
DR RefSeq; XP_016876478.1; XM_017020989.1.
DR RefSeq; XP_016876479.1; XM_017020990.1.
DR PDB; 4IF8; X-ray; 2.08 A; A/B=22-414.
DR PDB; 4Y3K; X-ray; 2.20 A; A/B=22-414.
DR PDB; 4Y40; X-ray; 2.20 A; A/B=22-414.
DR PDB; 5EI0; X-ray; 2.50 A; A/E=22-414.
DR PDBsum; 4IF8; -.
DR PDBsum; 4Y3K; -.
DR PDBsum; 4Y40; -.
DR PDBsum; 5EI0; -.
DR AlphaFoldDB; Q8IW75; -.
DR SMR; Q8IW75; -.
DR BioGRID; 126901; 143.
DR IntAct; Q8IW75; 39.
DR STRING; 9606.ENSP00000342109; -.
DR MEROPS; I04.091; -.
DR GlyGen; Q8IW75; 4 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q8IW75; -.
DR PhosphoSitePlus; Q8IW75; -.
DR BioMuta; SERPINA12; -.
DR DMDM; 74728144; -.
DR MassIVE; Q8IW75; -.
DR PaxDb; Q8IW75; -.
DR PeptideAtlas; Q8IW75; -.
DR PRIDE; Q8IW75; -.
DR ProteomicsDB; 70821; -.
DR TopDownProteomics; Q8IW75; -.
DR Antibodypedia; 27079; 375 antibodies from 33 providers.
DR DNASU; 145264; -.
DR Ensembl; ENST00000341228.2; ENSP00000342109.2; ENSG00000165953.10.
DR Ensembl; ENST00000556881.5; ENSP00000451738.1; ENSG00000165953.10.
DR Ensembl; ENST00000677451.1; ENSP00000503935.1; ENSG00000165953.10.
DR GeneID; 145264; -.
DR KEGG; hsa:145264; -.
DR MANE-Select; ENST00000677451.1; ENSP00000503935.1; NM_001382267.1; NP_001369196.1.
DR UCSC; uc001ydj.3; human.
DR CTD; 145264; -.
DR DisGeNET; 145264; -.
DR GeneCards; SERPINA12; -.
DR HGNC; HGNC:18359; SERPINA12.
DR HPA; ENSG00000165953; Tissue enriched (skin).
DR MIM; 617471; gene.
DR neXtProt; NX_Q8IW75; -.
DR OpenTargets; ENSG00000165953; -.
DR Orphanet; 86923; Hereditary palmoplantar keratoderma, Gamborg-Nielsen type.
DR PharmGKB; PA134863157; -.
DR VEuPathDB; HostDB:ENSG00000165953; -.
DR eggNOG; KOG2392; Eukaryota.
DR GeneTree; ENSGT00940000161977; -.
DR HOGENOM; CLU_023330_2_1_1; -.
DR InParanoid; Q8IW75; -.
DR OMA; VPMMFRG; -.
DR OrthoDB; 1124079at2759; -.
DR PhylomeDB; Q8IW75; -.
DR TreeFam; TF343201; -.
DR PathwayCommons; Q8IW75; -.
DR SignaLink; Q8IW75; -.
DR BioGRID-ORCS; 145264; 10 hits in 1066 CRISPR screens.
DR ChiTaRS; SERPINA12; human.
DR GenomeRNAi; 145264; -.
DR Pharos; Q8IW75; Tbio.
DR PRO; PR:Q8IW75; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q8IW75; protein.
DR Bgee; ENSG00000165953; Expressed in skin of leg and 81 other tissues.
DR Genevisible; Q8IW75; HS.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0006094; P:gluconeogenesis; IEA:Ensembl.
DR GO; GO:0008610; P:lipid biosynthetic process; IEA:Ensembl.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IBA:GO_Central.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IEA:Ensembl.
DR GO; GO:0051055; P:negative regulation of lipid biosynthetic process; IEA:Ensembl.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IEA:Ensembl.
DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IEA:Ensembl.
DR GO; GO:0090181; P:regulation of cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0090207; P:regulation of triglyceride metabolic process; IEA:Ensembl.
DR Gene3D; 2.30.39.10; -; 1.
DR Gene3D; 3.30.497.10; -; 1.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR InterPro; IPR036186; Serpin_sf.
DR InterPro; IPR042178; Serpin_sf_1.
DR InterPro; IPR042185; Serpin_sf_2.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR Pfam; PF00079; Serpin; 1.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Glycoprotein; Protease inhibitor; Reference proteome;
KW Secreted; Serine protease inhibitor; Signal.
FT SIGNAL 1..20
FT /evidence="ECO:0000250"
FT CHAIN 21..414
FT /note="Serpin A12"
FT /id="PRO_0000041976"
FT REGION 364..382
FT /note="Reactive center loop"
FT /evidence="ECO:0000269|PubMed:26529565,
FT ECO:0000305|PubMed:23370777, ECO:0000305|PubMed:26199422"
FT SITE 378..379
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:26529565"
FT CARBOHYD 221
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:28668641"
FT CARBOHYD 233
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:28668641"
FT CARBOHYD 267
FT /note="N-linked (GlcNAc...) (high mannose) asparagine"
FT /evidence="ECO:0000269|PubMed:28668641"
FT VARIANT 142
FT /note="Q -> K (in dbSNP:rs17090972)"
FT /id="VAR_051943"
FT VARIANT 219
FT /note="D -> G (in dbSNP:rs192558870)"
FT /evidence="ECO:0000269|PubMed:27693231"
FT /id="VAR_077875"
FT VARIANT 394
FT /note="I -> V (in dbSNP:rs34519784)"
FT /id="VAR_051944"
FT MUTAGEN 221
FT /note="N->A: Reduced N-glycosylation. Loss of N-
FT glycosylation; when associated with A-233 and A-267."
FT /evidence="ECO:0000269|PubMed:28668641"
FT MUTAGEN 233
FT /note="N->A: Reduced N-glycosylation. Loss of N-
FT glycosylation; when associated with A-221 and A-267."
FT /evidence="ECO:0000269|PubMed:28668641"
FT MUTAGEN 267
FT /note="N->A: Reduced N-glycosylation. Loss of N-
FT glycosylation; when associated with A-221 and A-233."
FT /evidence="ECO:0000269|PubMed:28668641"
FT MUTAGEN 302
FT /note="R->A,E: Significantly impairs KLK7 inhibition
FT activity. Slightly enhances KLK7 inhibition activity; when
FT associated with S-379."
FT /evidence="ECO:0000269|PubMed:26199422"
FT MUTAGEN 305
FT /note="D->C: Results in formation of an artificial
FT disulfide bond which stabilizes the reactive center loop
FT and enhances KLK7 inhibition activity; when associated with
FT C-383."
FT /evidence="ECO:0000269|PubMed:26199422"
FT MUTAGEN 365
FT /note="T->R: Fails to inhibit KLK7 activity. Increased
FT protein stability in cleaved form and conformational
FT changes which may allow escape of the substrate."
FT /evidence="ECO:0000269|PubMed:23370777,
FT ECO:0000269|PubMed:26529565"
FT MUTAGEN 369
FT /note="A->P: Fails to inhibit KLK7 activity. Increased
FT protein stability in cleaved form and conformational
FT changes which may allow escape of the substrate."
FT /evidence="ECO:0000269|PubMed:23370777,
FT ECO:0000269|PubMed:26529565"
FT MUTAGEN 379
FT /note="E->S: Significantly enhances KLK7 inhibition
FT activity. Slightly enhances KLK7 inhibition activity; when
FT associated with E-302."
FT /evidence="ECO:0000269|PubMed:26199422"
FT MUTAGEN 383
FT /note="V->C: Results in formation of an artificial
FT disulfide bond which stabilizes the reactive center loop
FT and enhances KLK7 inhibition activity; when associated with
FT C-305."
FT /evidence="ECO:0000269|PubMed:26199422"
FT HELIX 39..66
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 72..74
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 76..86
FT /evidence="ECO:0007829|PDB:4IF8"
FT TURN 87..89
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 92..101
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 105..107
FT /evidence="ECO:0007829|PDB:5EI0"
FT HELIX 109..123
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 125..141
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 148..158
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 170..184
FT /evidence="ECO:0007829|PDB:4IF8"
FT TURN 185..187
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 202..212
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 214..216
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 220..222
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 224..233
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 235..252
FT /evidence="ECO:0007829|PDB:4IF8"
FT TURN 253..256
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 257..275
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 280..286
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 289..297
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 300..309
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 311..318
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 319..322
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 323..326
FT /evidence="ECO:0007829|PDB:4IF8"
FT HELIX 330..332
FT /evidence="ECO:0007829|PDB:4IF8"
FT TURN 339..341
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 351..360
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 362..376
FT /evidence="ECO:0007829|PDB:5EI0"
FT STRAND 382..385
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 390..396
FT /evidence="ECO:0007829|PDB:4IF8"
FT TURN 397..400
FT /evidence="ECO:0007829|PDB:4IF8"
FT STRAND 401..409
FT /evidence="ECO:0007829|PDB:4IF8"
SQ SEQUENCE 414 AA; 47175 MW; 5C70F1AB5935661C CRC64;
MNPTLGLAIF LAVLLTVKGL LKPSFSPRNY KALSEVQGWK QRMAAKELAR QNMDLGFKLL
KKLAFYNPGR NIFLSPLSIS TAFSMLCLGA QDSTLDEIKQ GFNFRKMPEK DLHEGFHYII
HELTQKTQDL KLSIGNTLFI DQRLQPQRKF LEDAKNFYSA ETILTNFQNL EMAQKQINDF
ISQKTHGKIN NLIENIDPGT VMLLANYIFF RARWKHEFDP NVTKEEDFFL EKNSSVKVPM
MFRSGIYQVG YDDKLSCTIL EIPYQKNITA IFILPDEGKL KHLEKGLQVD TFSRWKTLLS
RRVVDVSVPR LHMTGTFDLK KTLSYIGVSK IFEEHGDLTK IAPHRSLKVG EAVHKAELKM
DERGTEGAAG TGAQTLPMET PLVVKIDKPY LLLIYSEKIP SVLFLGKIVN PIGK
