PEPA4_HUMAN
ID PEPA4_HUMAN Reviewed; 388 AA.
AC P0DJD7; A8K749; B7ZW75; P00790; Q7M4R0; Q8N1E3;
DT 22-FEB-2012, integrated into UniProtKB/Swiss-Prot.
DT 22-FEB-2012, sequence version 1.
DT 03-AUG-2022, entry version 78.
DE RecName: Full=Pepsin A-4;
DE EC=3.4.23.1;
DE AltName: Full=Pepsinogen-4;
DE Flags: Precursor;
GN Name=PGA4;
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 [GENOMIC DNA].
RX PubMed=6300126; DOI=10.1016/s0021-9258(18)32572-9;
RA Sogawa K., Fujii-Kuriyama Y., Mizukami Y., Ichihara Y., Takahashi K.;
RT "Primary structure of human pepsinogen gene.";
RL J. Biol. Chem. 258:5306-5311(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Kidney;
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 [5]
RP PARTIAL PROTEIN SEQUENCE OF 1-28.
RX PubMed=2415509; DOI=10.1093/oxfordjournals.jbchem.a135303;
RA Ichihara Y., Sogawa K., Takahashi K.;
RT "Isolation of human, swine, and rat prepepsinogens and calf preprochymosin,
RT and determination of the primary structures of their NH2-terminal signal
RT sequences.";
RL J. Biochem. 98:483-492(1985).
RN [6]
RP PROTEIN SEQUENCE OF 16-100.
RX PubMed=2515193; DOI=10.1093/oxfordjournals.jbchem.a122952;
RA Athauda S.B.P., Tanji M., Kageyama T., Takahashi K.;
RT "A comparative study on the NH2-terminal amino acid sequences and some
RT other properties of six isozymic forms of human pepsinogens and pepsins.";
RL J. Biochem. 106:920-927(1989).
RN [7]
RP PROTEIN SEQUENCE OF 16-68.
RX PubMed=3197840; DOI=10.1016/0014-5793(88)81033-0;
RA Foltmann B.;
RT "Activation of human pepsinogens.";
RL FEBS Lett. 241:69-72(1988).
RN [8]
RP PROTEIN SEQUENCE OF 362-388.
RX PubMed=4909888; DOI=10.1016/s0021-9258(18)63137-0;
RA Huang W.-Y., Tang J.;
RT "Carboxyl-terminal sequence of human gastricsin and pepsin.";
RL J. Biol. Chem. 245:2189-2193(1970).
RN [9]
RP IDENTIFICATION.
RC TISSUE=Placenta;
RX PubMed=2714789; DOI=10.1016/0888-7543(89)90325-x;
RA Evers M.P.J., Zelle B., Bebelman J.-P., van Beusechem V., Kraakman L.,
RA Hoffer M.J.V., Pronk J.C., Mager W.H., Planta R.J., Eriksson A.W.,
RA Frants R.R.;
RT "Nucleotide sequence comparison of five human pepsinogen A (PGA) genes:
RT evolution of the PGA multigene family.";
RL Genomics 4:232-239(1989).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 63-388, ACTIVE SITES, AND
RP DISULFIDE BONDS.
RX PubMed=7663352; DOI=10.1002/pro.5560040516;
RA Fujinaga M., Chernaia M.M., Tarasova N.I., Mosimann S.C., James M.N.G.;
RT "Crystal structure of human pepsin and its complex with pepstatin.";
RL Protein Sci. 4:960-972(1995).
CC -!- FUNCTION: Shows particularly broad specificity; although bonds
CC involving phenylalanine and leucine are preferred, many others are also
CC cleaved to some extent.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Preferential cleavage: hydrophobic, preferably aromatic,
CC residues in P1 and P1' positions. Cleaves 1-Phe-|-Val-2, 4-Gln-|-His-
CC 5, 13-Glu-|-Ala-14, 14-Ala-|-Leu-15, 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-
CC 17, 23-Gly-|-Phe-24, 24-Phe-|-Phe-25 and 25-Phe-|-Tyr-26 bonds in the
CC B chain of insulin.; EC=3.4.23.1; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU10094};
CC -!- INTERACTION:
CC P0DJD7; Q86WK6: AMIGO1; NbExp=3; IntAct=EBI-12957629, EBI-19125216;
CC P0DJD7; P04233-2: CD74; NbExp=3; IntAct=EBI-12957629, EBI-12222807;
CC P0DJD7; Q96LL3: FIMP; NbExp=3; IntAct=EBI-12957629, EBI-12887376;
CC P0DJD7; Q8TBE3: FNDC9; NbExp=3; IntAct=EBI-12957629, EBI-12142257;
CC P0DJD7; Q9UM44: HHLA2; NbExp=3; IntAct=EBI-12957629, EBI-2867874;
CC P0DJD7; P15151: PVR; NbExp=3; IntAct=EBI-12957629, EBI-3919694;
CC P0DJD7; Q9NPE6: SPAG4; NbExp=3; IntAct=EBI-12957629, EBI-10819434;
CC P0DJD7; P27105: STOM; NbExp=3; IntAct=EBI-12957629, EBI-1211440;
CC P0DJD7; Q9BVX2: TMEM106C; NbExp=3; IntAct=EBI-12957629, EBI-2821497;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR EMBL; J00287; AAA98529.1; -; Genomic_DNA.
DR EMBL; J00279; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00280; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00281; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00282; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00283; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00284; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00285; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; J00286; AAA98529.1; JOINED; Genomic_DNA.
DR EMBL; AK291864; BAF84553.1; -; mRNA.
DR EMBL; AP000437; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP003037; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC150659; AAI50660.1; -; mRNA.
DR EMBL; BC171910; AAI71910.1; -; mRNA.
DR EMBL; BC171920; AAI71920.1; -; mRNA.
DR CCDS; CCDS31575.1; -.
DR PIR; A00980; PEHU.
DR PIR; A30142; A30142.
DR PIR; A92058; A92058.
DR PIR; B30142; B30142.
DR RefSeq; NP_001073276.1; NM_001079808.3.
DR RefSeq; XP_016854970.1; XM_016999481.1.
DR PDB; 1FLH; X-ray; 2.45 A; A=63-388.
DR PDB; 1PSN; X-ray; 2.20 A; A=63-388.
DR PDB; 1PSO; X-ray; 2.00 A; E=63-388.
DR PDB; 1QRP; X-ray; 1.96 A; E=63-388.
DR PDB; 3UTL; X-ray; 2.61 A; A=63-388.
DR PDBsum; 1FLH; -.
DR PDBsum; 1PSN; -.
DR PDBsum; 1PSO; -.
DR PDBsum; 1QRP; -.
DR PDBsum; 3UTL; -.
DR AlphaFoldDB; P0DJD7; -.
DR SMR; P0DJD7; -.
DR BioGRID; 569099; 10.
DR IntAct; P0DJD7; 9.
DR STRING; 9606.ENSP00000367391; -.
DR BindingDB; P0DJD7; -.
DR MEROPS; A01.001; -.
DR MEROPS; A01.070; -.
DR iPTMnet; P0DJD7; -.
DR PhosphoSitePlus; P0DJD7; -.
DR BioMuta; PGA4; -.
DR DMDM; 378521995; -.
DR jPOST; P0DJD7; -.
DR MassIVE; P0DJD7; -.
DR PaxDb; P0DJD7; -.
DR PeptideAtlas; P0DJD7; -.
DR PRIDE; P0DJD7; -.
DR Antibodypedia; 28082; 139 antibodies from 21 providers.
DR DNASU; 643847; -.
DR Ensembl; ENST00000378149.9; ENSP00000367391.3; ENSG00000229183.10.
DR GeneID; 643847; -.
DR KEGG; hsa:643847; -.
DR MANE-Select; ENST00000378149.9; ENSP00000367391.3; NM_001079808.6; NP_001073276.1.
DR UCSC; uc001nqy.4; human.
DR CTD; 643847; -.
DR DisGeNET; 643847; -.
DR GeneCards; PGA4; -.
DR HGNC; HGNC:8886; PGA4.
DR HPA; ENSG00000229183; Tissue enriched (stomach).
DR MIM; 169700; gene.
DR MIM; 169720; gene.
DR neXtProt; NX_P0DJD7; -.
DR OpenTargets; ENSG00000229183; -.
DR VEuPathDB; HostDB:ENSG00000229183; -.
DR eggNOG; KOG1339; Eukaryota.
DR GeneTree; ENSGT00940000155036; -.
DR HOGENOM; CLU_013253_3_0_1; -.
DR InParanoid; P0DJD7; -.
DR OMA; ENYMDME; -.
DR OrthoDB; 1619495at2759; -.
DR PhylomeDB; P0DJD7; -.
DR TreeFam; TF314990; -.
DR PathwayCommons; P0DJD7; -.
DR Reactome; R-HSA-5683826; Surfactant metabolism.
DR SignaLink; P0DJD7; -.
DR BioGRID-ORCS; 643847; 4 hits in 206 CRISPR screens.
DR ChiTaRS; PGA4; human.
DR GenomeRNAi; 643847; -.
DR Pharos; P0DJD7; Tbio.
DR PRO; PR:P0DJD7; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P0DJD7; protein.
DR Bgee; ENSG00000229183; Expressed in right uterine tube and 91 other tissues.
DR ExpressionAtlas; P0DJD7; baseline and differential.
DR Genevisible; P0DJD7; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0097486; C:multivesicular body lumen; TAS:Reactome.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0007586; P:digestion; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR CDD; cd05478; pepsin_A; 1.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase_A1.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR012848; Aspartic_peptidase_N.
DR InterPro; IPR034162; Pepsin_A.
DR InterPro; IPR033121; PEPTIDASE_A1.
DR InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR PANTHER; PTHR47966; PTHR47966; 1.
DR Pfam; PF07966; A1_Propeptide; 1.
DR Pfam; PF00026; Asp; 1.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 2.
DR PROSITE; PS51767; PEPTIDASE_A1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Aspartyl protease; Digestion; Direct protein sequencing;
KW Disulfide bond; Hydrolase; Phosphoprotein; Protease; Reference proteome;
KW Secreted; Signal; Zymogen.
FT SIGNAL 1..15
FT /evidence="ECO:0000269|PubMed:2515193,
FT ECO:0000269|PubMed:3197840"
FT PROPEP 16..62
FT /note="Activation peptide"
FT /id="PRO_0000415757"
FT CHAIN 63..388
FT /note="Pepsin A-4"
FT /id="PRO_0000415758"
FT DOMAIN 76..385
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 94
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094,
FT ECO:0000269|PubMed:7663352"
FT ACT_SITE 277
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094,
FT ECO:0000269|PubMed:7663352"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P03954"
FT DISULFID 107..112
FT /evidence="ECO:0000269|PubMed:7663352"
FT DISULFID 268..272
FT /evidence="ECO:0000269|PubMed:7663352"
FT DISULFID 311..344
FT /evidence="ECO:0000269|PubMed:7663352"
FT CONFLICT 291
FT /note="A -> T (in Ref. 2; BAF84553)"
FT /evidence="ECO:0000305"
FT CONFLICT 371..372
FT /note="YF -> FY (in Ref. 8; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:1QRP"
FT TURN 72..74
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 75..82
FT /evidence="ECO:0007829|PDB:1QRP"
FT TURN 83..86
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 87..94
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 100..102
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 110..113
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 120..122
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 127..136
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 141..153
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 156..168
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 172..176
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 180..184
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 188..190
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 192..194
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 198..204
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 209..216
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 226..229
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 234..236
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 237..239
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 242..245
FT /evidence="ECO:0007829|PDB:1QRP"
FT TURN 249..252
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 253..256
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 258..261
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 264..267
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 272..276
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 282..285
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 287..296
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 307..309
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 311..316
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 320..324
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 327..331
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 333..336
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 337..340
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 343..350
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 361..363
FT /evidence="ECO:0007829|PDB:1QRP"
FT HELIX 365..370
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 371..376
FT /evidence="ECO:0007829|PDB:1QRP"
FT TURN 377..380
FT /evidence="ECO:0007829|PDB:1QRP"
FT STRAND 381..387
FT /evidence="ECO:0007829|PDB:1QRP"
SQ SEQUENCE 388 AA; 41977 MW; C9CB89BA08F4D78B CRC64;
MKWLLLLGLV ALSECIMYKV PLIRKKSLRR TLSERGLLKD FLKKHNLNPA RKYFPQWEAP
TLVDEQPLEN YLDMEYFGTI GIGTPAQDFT VVFDTGSSNL WVPSVYCSSL ACTNHNRFNP
EDSSTYQSTS ETVSITYGTG SMTGILGYDT VQVGGISDTN QIFGLSETEP GSFLYYAPFD
GILGLAYPSI SSSGATPVFD NIWNQGLVSQ DLFSVYLSAD DQSGSVVIFG GIDSSYYTGS
LNWVPVTVEG YWQITVDSIT MNGEAIACAE GCQAIVDTGT SLLTGPTSPI ANIQSDIGAS
ENSDGDMVVS CSAISSLPDI VFTINGVQYP VPPSAYILQS EGSCISGFQG MNLPTESGEL
WILGDVFIRQ YFTVFDRANN QVGLAPVA
