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   24-JAN-2024, entry version 84.
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; 9606-ENSP00000367391; -.
DR   PeptideAtlas; P0DJD7; -.
DR   Antibodypedia; 28082; 145 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   AGR; HGNC:8886; -.
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; 1120702at2759; -.
DR   PhylomeDB; P0DJD7; -.
DR   TreeFam; TF314990; -.
DR   PathwayCommons; P0DJD7; -.
DR   Reactome; R-HSA-5683826; Surfactant metabolism.
DR   SignaLink; P0DJD7; -.
DR   BioGRID-ORCS; 643847; 5 hits in 241 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 93 other cell types or tissues.
DR   ExpressionAtlas; P0DJD7; baseline and differential.
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; 6.10.140.60; -; 1.
DR   Gene3D; 2.40.70.10; Acid Proteases; 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; BETA-SITE APP-CLEAVING ENZYME, ISOFORM A-RELATED; 1.
DR   PANTHER; PTHR47966:SF22; PEPSIN A-3-RELATED; 1.
DR   Pfam; PF07966; A1_Propeptide; 1.
DR   Pfam; PF00026; Asp; 1.
DR   PRINTS; PR00792; PEPSIN.
DR   SUPFAM; SSF50630; Acid proteases; 1.
DR   PROSITE; PS00141; ASP_PROTEASE; 2.
DR   PROSITE; PS51767; PEPTIDASE_A1; 1.
DR   Genevisible; P0DJD7; HS.
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
//