CEL2A_HUMAN
ID CEL2A_HUMAN Reviewed; 269 AA.
AC P08217; B2R5I4; Q14243;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1988, sequence version 1.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Chymotrypsin-like elastase family member 2A {ECO:0000305};
DE EC=3.4.21.71;
DE AltName: Full=Elastase-2A;
DE Flags: Precursor;
GN Name=CELA2A {ECO:0000312|HGNC:HGNC:24609}; Synonyms=ELA2A;
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].
RX PubMed=3427074; DOI=10.1021/bi00397a010;
RA Fletcher T.S., Shen W.F., Largman C.;
RT "Primary structure of human pancreatic elastase 2 determined by sequence
RT analysis of the cloned mRNA.";
RL Biochemistry 26:7256-7261(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3646943; DOI=10.1089/dna.1987.6.163;
RA Kawashima I., Tani T., Shimoda K., Takiguchi Y.;
RT "Characterization of pancreatic elastase II cDNAs: two elastase II mRNAs
RT are expressed in human pancreas.";
RL DNA 6:163-172(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pancreas;
RX PubMed=2834346; DOI=10.1093/oxfordjournals.jbchem.a122204;
RA Shirasu Y., Yoshida H., Matsuki S., Takemura K., Ikeda N., Shimada Y.,
RA Ozawa T., Mikayama T., Iijima H., Ishida A., Sato Y., Tamai Y., Tanaka J.,
RA Ikenaga H.;
RT "Molecular cloning and expression in Escherichia coli of a cDNA encoding
RT human pancreatic elastase 2.";
RL J. Biochem. 102:1555-1563(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Prostate;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [8]
RP PROTEIN SEQUENCE OF 18-50, AND INTERACTION WITH CPA1.
RX PubMed=2307232; DOI=10.1016/0014-5793(90)80665-6;
RA Moulard M., Michon T., Kerfelec B., Chapus C.;
RT "Further studies on the human pancreatic binary complexes involving
RT procarboxypeptidase A.";
RL FEBS Lett. 261:179-183(1990).
RN [9]
RP TISSUE SPECIFICITY.
RX PubMed=10620133; DOI=10.1046/j.1523-1747.2000.00825.x;
RA Talas U., Dunlop J., Khalaf S., Leigh I.M., Kelsell D.P.;
RT "Human elastase 1: evidence for expression in the skin and the
RT identification of a frequent frameshift polymorphism.";
RL J. Invest. Dermatol. 114:165-170(2000).
RN [10]
RP INVOLVEMENT IN AOMS4, FUNCTION, VARIANTS AOMS4 MET-70; MET-85 AND ASN-121,
RP CHARACTERIZATION OF VARIANTS AOMS4 MET-70; MET-85 AND ASN-121, INTERACTION
RP WITH SERPINA1, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=31358993; DOI=10.1038/s41588-019-0470-3;
RA Esteghamat F., Broughton J.S., Smith E., Cardone R., Tyagi T., Guerra M.,
RA Szabo A., Ugwu N., Mani M.V., Azari B., Kayingo G., Chung S., Fathzadeh M.,
RA Weiss E., Bender J., Mane S., Lifton R.P., Adeniran A., Nathanson M.H.,
RA Gorelick F.S., Hwa J., Sahin-Toth M., Belfort-DeAguiar R., Kibbey R.G.,
RA Mani A.;
RT "CELA2A mutations predispose to early-onset atherosclerosis and metabolic
RT syndrome and affect plasma insulin and platelet activation.";
RL Nat. Genet. 51:1233-1243(2019).
CC -!- FUNCTION: Elastase that enhances insulin signaling and might have a
CC physiologic role in cellular glucose metabolism. Circulates in plasma
CC and reduces platelet hyperactivation, triggers both insulin secretion
CC and degradation, and increases insulin sensitivity.
CC {ECO:0000269|PubMed:31358993}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Preferential cleavage: Leu-|-Xaa, Met-|-Xaa and Phe-|-Xaa.
CC Hydrolyzes elastin.; EC=3.4.21.71;
CC Evidence={ECO:0000269|PubMed:31358993};
CC -!- SUBUNIT: Interacts with CPA1. Interacts with SERPINA1
CC (PubMed:31358993). {ECO:0000269|PubMed:2307232,
CC ECO:0000269|PubMed:31358993}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:31358993}.
CC -!- TISSUE SPECIFICITY: Expressed in pancreas. Not detected in
CC keratinocytes (PubMed:10620133). Detected in exocrine secretions of the
CC pancreas (at protein level). Also expressed in a small fraction of
CC cells in pancreatic islets, adrenal cortex, intestinal glands and
CC colonic lymphoid follicles (at protein level) (PubMed:31358993).
CC Detected in plasma (PubMed:31358993). {ECO:0000269|PubMed:10620133,
CC ECO:0000269|PubMed:31358993}.
CC -!- DISEASE: Abdominal obesity-metabolic syndrome 4 (AOMS4) [MIM:618620]: A
CC form of abdominal obesity-metabolic syndrome, a disorder characterized
CC by abdominal obesity, high triglycerides, low levels of high density
CC lipoprotein cholesterol, high blood pressure, and elevated fasting
CC glucose levels. AOMS4 is an autosomal dominant disease. Patients
CC manifest obesity, hypertension, early-onset coronary artery disease and
CC type 2 diabetes. {ECO:0000269|PubMed:31358993}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Elastase subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00274}.
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DR EMBL; M16631; AAA52374.1; -; mRNA.
DR EMBL; M16652; AAA52380.1; -; mRNA.
DR EMBL; D00236; BAA00165.1; -; mRNA.
DR EMBL; AK312198; BAG35131.1; -; mRNA.
DR EMBL; AK056678; BAG51782.1; -; mRNA.
DR EMBL; AL512883; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471167; EAW51727.1; -; Genomic_DNA.
DR EMBL; BC007031; AAH07031.1; -; mRNA.
DR CCDS; CCDS157.1; -.
DR PIR; B26823; B26823.
DR RefSeq; NP_254275.1; NM_033440.2.
DR AlphaFoldDB; P08217; -.
DR SMR; P08217; -.
DR BioGRID; 121962; 16.
DR STRING; 9606.ENSP00000352639; -.
DR DrugBank; DB06901; 2-(2-HYDROXY-CYCLOPENTYL)-PENT-4-ENAL.
DR MEROPS; S01.155; -.
DR iPTMnet; P08217; -.
DR PhosphoSitePlus; P08217; -.
DR BioMuta; CELA2A; -.
DR DMDM; 119255; -.
DR MassIVE; P08217; -.
DR PaxDb; P08217; -.
DR PeptideAtlas; P08217; -.
DR PRIDE; P08217; -.
DR ProteomicsDB; 52086; -.
DR Antibodypedia; 14313; 100 antibodies from 16 providers.
DR DNASU; 63036; -.
DR Ensembl; ENST00000359621.5; ENSP00000352639.4; ENSG00000142615.8.
DR GeneID; 63036; -.
DR KEGG; hsa:63036; -.
DR MANE-Select; ENST00000359621.5; ENSP00000352639.4; NM_033440.3; NP_254275.1.
DR UCSC; uc001awk.4; human.
DR CTD; 63036; -.
DR DisGeNET; 63036; -.
DR GeneCards; CELA2A; -.
DR HGNC; HGNC:24609; CELA2A.
DR HPA; ENSG00000142615; Tissue enriched (pancreas).
DR MalaCards; CELA2A; -.
DR MIM; 609443; gene.
DR MIM; 618620; phenotype.
DR neXtProt; NX_P08217; -.
DR OpenTargets; ENSG00000142615; -.
DR PharmGKB; PA165750794; -.
DR VEuPathDB; HostDB:ENSG00000142615; -.
DR eggNOG; KOG3627; Eukaryota.
DR GeneTree; ENSGT01030000234528; -.
DR HOGENOM; CLU_006842_0_4_1; -.
DR InParanoid; P08217; -.
DR OMA; GSTLGCN; -.
DR OrthoDB; 1314811at2759; -.
DR PhylomeDB; P08217; -.
DR TreeFam; TF330455; -.
DR PathwayCommons; P08217; -.
DR Reactome; R-HSA-6809371; Formation of the cornified envelope.
DR BioGRID-ORCS; 63036; 11 hits in 1067 CRISPR screens.
DR GeneWiki; CELA2A; -.
DR GenomeRNAi; 63036; -.
DR Pharos; P08217; Tbio.
DR PRO; PR:P08217; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P08217; protein.
DR Bgee; ENSG00000142615; Expressed in body of pancreas and 91 other tissues.
DR Genevisible; P08217; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0036457; C:keratohyalin granule; IDA:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0017171; F:serine hydrolase activity; IDA:MGI.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:1901143; P:insulin catabolic process; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR GO; GO:0050796; P:regulation of insulin secretion; IDA:UniProtKB.
DR GO; GO:0090330; P:regulation of platelet aggregation; IDA:UniProtKB.
DR GO; GO:0032868; P:response to insulin; IDA:UniProtKB.
DR CDD; cd00190; Tryp_SPc; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR001254; Trypsin_dom.
DR InterPro; IPR018114; TRYPSIN_HIS.
DR InterPro; IPR033116; TRYPSIN_SER.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW Diabetes mellitus; Direct protein sequencing; Disease variant;
KW Disulfide bond; Hydrolase; Obesity; Protease; Reference proteome; Secreted;
KW Serine protease; Signal; Zymogen.
FT SIGNAL 1..16
FT PROPEP 17..28
FT /note="Activation peptide"
FT /id="PRO_0000027693"
FT CHAIN 29..269
FT /note="Chymotrypsin-like elastase family member 2A"
FT /id="PRO_0000027694"
FT DOMAIN 29..267
FT /note="Peptidase S1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT ACT_SITE 73
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 121
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 216
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT DISULFID 58..74
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT DISULFID 155..222
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT DISULFID 186..202
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT DISULFID 212..243
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT VARIANT 70
FT /note="T -> M (in AOMS4; strongly decreased elastase
FT activity; abolishes interaction with SERPINA1; impaired
FT insulin degradation; increased platelet aggregation;
FT dbSNP:rs372947070)"
FT /evidence="ECO:0000269|PubMed:31358993"
FT /id="VAR_083326"
FT VARIANT 85
FT /note="L -> M (in AOMS4; unknown pathological significance;
FT strongly decreased elastase activity; no effect on
FT interaction with SERPINA1; no effect on insulin
FT degradation; increased platelet aggregation;
FT dbSNP:rs558493952)"
FT /evidence="ECO:0000269|PubMed:31358993"
FT /id="VAR_083327"
FT VARIANT 121
FT /note="D -> N (in AOMS4; strongly decreased elastase
FT activity; abolishes interaction with SERPINA1; increased
FT levels in plasma; impaired insulin degradation; increased
FT platelet aggregation; dbSNP:rs1352544800)"
FT /evidence="ECO:0000269|PubMed:31358993"
FT /id="VAR_083328"
FT VARIANT 257
FT /note="N -> S (in dbSNP:rs2303193)"
FT /id="VAR_051837"
FT CONFLICT 202
FT /note="C -> V (in Ref. 3; BAA00165)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 269 AA; 28888 MW; A2E05143EFF4987C CRC64;
MIRTLLLSTL VAGALSCGDP TYPPYVTRVV GGEEARPNSW PWQVSLQYSS NGKWYHTCGG
SLIANSWVLT AAHCISSSRT YRVGLGRHNL YVAESGSLAV SVSKIVVHKD WNSNQISKGN
DIALLKLANP VSLTDKIQLA CLPPAGTILP NNYPCYVTGW GRLQTNGAVP DVLQQGRLLV
VDYATCSSSA WWGSSVKTSM ICAGGDGVIS SCNGDSGGPL NCQASDGRWQ VHGIVSFGSR
LGCNYYHKPS VFTRVSNYID WINSVIANN
