PLM4_PLAF7
ID PLM4_PLAF7 Reviewed; 449 AA.
AC Q8IM16;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Plasmepsin IV {ECO:0000303|PubMed:23471987};
DE EC=3.4.23.39 {ECO:0000269|PubMed:29943906};
DE AltName: Full=Plasmepsin 4 {ECO:0000305};
DE Flags: Precursor;
GN Name=PMIV {ECO:0000303|PubMed:23471987};
GN ORFNames=PF3D7_1407800 {ECO:0000312|EMBL:CZT99785.1};
OS Plasmodium falciparum (isolate 3D7).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=36329 {ECO:0000312|Proteomes:UP000001450};
RN [1] {ECO:0000312|Proteomes:UP000001450}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=3D7 {ECO:0000312|Proteomes:UP000001450};
RX PubMed=12368864; DOI=10.1038/nature01097;
RA Gardner M.J., Hall N., Fung E., White O., Berriman M., Hyman R.W.,
RA Carlton J.M., Pain A., Nelson K.E., Bowman S., Paulsen I.T., James K.D.,
RA Eisen J.A., Rutherford K.M., Salzberg S.L., Craig A., Kyes S., Chan M.-S.,
RA Nene V., Shallom S.J., Suh B., Peterson J., Angiuoli S., Pertea M.,
RA Allen J., Selengut J., Haft D., Mather M.W., Vaidya A.B., Martin D.M.A.,
RA Fairlamb A.H., Fraunholz M.J., Roos D.S., Ralph S.A., McFadden G.I.,
RA Cummings L.M., Subramanian G.M., Mungall C., Venter J.C., Carucci D.J.,
RA Hoffman S.L., Newbold C., Davis R.W., Fraser C.M., Barrell B.G.;
RT "Genome sequence of the human malaria parasite Plasmodium falciparum.";
RL Nature 419:498-511(2002).
RN [2] {ECO:0000305}
RP DISRUPTION PHENOTYPE.
RX PubMed=17581121; DOI=10.1111/j.1365-2958.2007.05768.x;
RA Bonilla J.A., Bonilla T.D., Yowell C.A., Fujioka H., Dame J.B.;
RT "Critical roles for the digestive vacuole plasmepsins of Plasmodium
RT falciparum in vacuolar function.";
RL Mol. Microbiol. 65:64-75(2007).
RN [3] {ECO:0000305}
RP IDENTIFICATION IN THE HEMOZOIN FORMATION COMPLEX, SUBCELLULAR LOCATION,
RP DEVELOPMENTAL STAGE, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23471987; DOI=10.1073/pnas.1218412110;
RA Chugh M., Sundararaman V., Kumar S., Reddy V.S., Siddiqui W.A.,
RA Stuart K.D., Malhotra P.;
RT "Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium
RT falciparum.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:5392-5397(2013).
RN [4] {ECO:0000305}
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=29943906; DOI=10.1111/febs.14598;
RA Mishra V., Rathore I., Arekar A., Sthanam L.K., Xiao H., Kiso Y., Sen S.,
RA Patankar S., Gustchina A., Hidaka K., Wlodawer A., Yada R.Y., Bhaumik P.;
RT "Deciphering the mechanism of potent peptidomimetic inhibitors targeting
RT plasmepsins - biochemical and structural insights.";
RL FEBS J. 285:3077-3096(2018).
RN [5] {ECO:0007744|PDB:1LS5}
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 122-449 WITH INHIBITOR, AND
RP DISULFIDE BONDS.
RX PubMed=12614616; DOI=10.1016/s0022-2836(03)00036-6;
RA Asojo O.A., Gulnik S.V., Afonina E., Yu B., Ellman J.A., Haque T.S.,
RA Silva A.M.;
RT "Novel uncomplexed and complexed structures of plasmepsin II, an aspartic
RT protease from Plasmodium falciparum.";
RL J. Mol. Biol. 327:173-181(2003).
CC -!- FUNCTION: During the asexual blood stage, catalyzes the cleavage of
CC denatured host hemoglobin (Hb) (By similarity). Digestion of host Hb is
CC an essential step which provides the parasite with amino acids for
CC protein synthesis, and regulates osmolarity (Probable).
CC {ECO:0000250|UniProtKB:Q17SB3, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of the bonds linking certain hydrophobic residues
CC in hemoglobin or globin. Also cleaves small molecules substrates such
CC as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO2)-Ser-Phe-Pro-Thr.; EC=3.4.23.39;
CC Evidence={ECO:0000269|PubMed:29943906};
CC -!- ACTIVITY REGULATION: Inhibited by KNI derived compounds KNI-10333 and
CC to a lesser extent KNI-10743. {ECO:0000269|PubMed:29943906}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass type II
CC membrane protein {ECO:0000255}. Vacuole lumen
CC {ECO:0000269|PubMed:23471987}. Note=In trophozoites, localizes to the
CC digestive (or food) vacuole, an acidic vacuole where host hemoglobin is
CC digested. {ECO:0000269|PubMed:23471987}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the asexual blood stage;
CC expression begins in trophozoites and continues in schizonts (at
CC protein level). {ECO:0000269|PubMed:23471987}.
CC -!- PTM: Proteolytically cleaved into the soluble active mature form by
CC cysteine proteases in the digestive vacuole of trophozoites.
CC Proteolysis requires an acidic environment. Autoprocessing or
CC transprocessing by other plasmepsins such as PMII may serve as an
CC alternate activation system. {ECO:0000250|UniProtKB:Q17SB3}.
CC -!- DISRUPTION PHENOTYPE: Quadruple knockout of PMI, PMII, PMIII and PMIV
CC causes a decrease in proliferation, an impaired proliferation in an
CC amino acid-limited medium, a reduced formation of haemozoin and an
CC abnormal accumulation of endosomal vesicles inside the digestive
CC vacuole. {ECO:0000269|PubMed:17581121}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family.
CC {ECO:0000255|RuleBase:RU000454}.
CC -!- CAUTION: It is unclear if PMIV is glycosylated as other members of the
CC same enzyme family, ie. PMI and PMII, are not. {ECO:0000305}.
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DR EMBL; LN999946; CZT99785.1; -; Genomic_DNA.
DR RefSeq; XP_001348248.1; XM_001348212.1.
DR PDB; 1LS5; X-ray; 2.80 A; A/B=122-449.
DR PDBsum; 1LS5; -.
DR AlphaFoldDB; Q8IM16; -.
DR SMR; Q8IM16; -.
DR STRING; 5833.PF14_0075; -.
DR BindingDB; Q8IM16; -.
DR ChEMBL; CHEMBL1741262; -.
DR DrugBank; DB11638; Artenimol.
DR MEROPS; A01.059; -.
DR SwissPalm; Q8IM16; -.
DR PRIDE; Q8IM16; -.
DR EnsemblProtists; CZT99785; CZT99785; PF3D7_1407800.
DR GeneID; 811657; -.
DR KEGG; pfa:PF3D7_1407800; -.
DR VEuPathDB; PlasmoDB:PF3D7_1407800; -.
DR HOGENOM; CLU_013253_3_2_1; -.
DR InParanoid; Q8IM16; -.
DR OMA; SHGCEAI; -.
DR PhylomeDB; Q8IM16; -.
DR BRENDA; 3.4.23.B14; 4889.
DR EvolutionaryTrace; Q8IM16; -.
DR Proteomes; UP000001450; Chromosome 14.
DR GO; GO:0020020; C:food vacuole; IDA:GeneDB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005775; C:vacuolar lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0044002; P:acquisition of nutrients from host; IDA:UniProtKB.
DR GO; GO:0042540; P:hemoglobin catabolic process; ISS:GeneDB.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR CDD; cd05471; pepsin_like; 1.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase_A1.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR034164; Pepsin-like_dom.
DR InterPro; IPR033121; PEPTIDASE_A1.
DR InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR PANTHER; PTHR47966; PTHR47966; 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; Disulfide bond; Hydrolase; Membrane;
KW Protease; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix; Vacuole; Zymogen.
FT PROPEP 1..121
FT /evidence="ECO:0000250|UniProtKB:Q17SB3"
FT /id="PRO_0000453386"
FT CHAIN 122..449
FT /note="Plasmepsin IV"
FT /id="PRO_0000453387"
FT TOPO_DOM 1..37
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 38..58
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 59..449
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT DOMAIN 137..444
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 155
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 335
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT DISULFID 168..173
FT /evidence="ECO:0000269|PubMed:12614616,
FT ECO:0007744|PDB:1LS5"
FT DISULFID 370..406
FT /evidence="ECO:0000269|PubMed:12614616,
FT ECO:0007744|PDB:1LS5"
FT STRAND 125..128
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 130..132
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 141..143
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 144..147
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 171..174
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 181..183
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 188..197
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 202..214
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 217..228
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 230..232
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 233..235
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 236..238
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 250..252
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 260..266
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 270..278
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 281..285
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 288..293
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 296..298
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 299..301
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 304..306
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 311..314
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 315..317
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 319..324
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 331..334
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 339..343
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 346..349
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 350..353
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 361..364
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 367..369
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 378..382
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 385..389
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 391..394
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 405..407
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 410..412
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 416..418
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 420..422
FT /evidence="ECO:0007829|PDB:1LS5"
FT HELIX 424..427
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 432..435
FT /evidence="ECO:0007829|PDB:1LS5"
FT TURN 436..439
FT /evidence="ECO:0007829|PDB:1LS5"
FT STRAND 440..443
FT /evidence="ECO:0007829|PDB:1LS5"
SQ SEQUENCE 449 AA; 51046 MW; 93301D8F108F0E8A CRC64;
MALTVKEEEF SNTLIKNASA FDRLKLGNLK NLKIQKKLQF LYLILFVLIT GVFFFFLIGN
FYSHRKLYQV IKNTKHTTIG FKIDRPHDKV LSSVLKNKLS TYVKESFKFF KSGYAQKGYL
GSENDSIELD DVANLMFYGE GQIGTNKQPF MFIFDTGSAN LWVPSVNCDS IGCSTKHLYD
ASASKSYEKD GTKVEISYGS GTVRGYFSKD VISLGDLSLP YKFIEVTDAD DLEPIYSGSE
FDGILGLGWK DLSIGSIDPV VVELKKQNKI DNALFTFYLP VHDKHVGYLT IGGIESDFYE
GPLTYEKLNH DLYWQIDLDI HFGKYVMQKA NAVVDSGTST ITAPTSFLNK FFRDMNVIKV
PFLPLYVTTC DNDDLPTLEF HSRNNKYTLE PEFYMDPLSD IDPALCMLYI LPVDIDDNTF
ILGDPFMRKY FTVFDYEKES VGFAVAKNL
