PLM3_PLAF7
ID PLM3_PLAF7 Reviewed; 451 AA.
AC Q8IM15;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Plasmepsin III {ECO:0000305};
DE EC=3.4.23.39 {ECO:0000269|PubMed:16624575, ECO:0000269|PubMed:18312598, ECO:0000269|PubMed:20435072};
DE AltName: Full=Histo-aspartic protease {ECO:0000303|PubMed:16624575};
DE AltName: Full=PfHAP {ECO:0000303|PubMed:17581121};
DE AltName: Full=Plasmepsin 3 {ECO:0000305};
DE Flags: Precursor;
GN Name=PMIII {ECO:0000305}; Synonyms=HAP {ECO:0000303|PubMed:16624575};
GN ORFNames=PF3D7_1408100 {ECO:0000312|EMBL:CZT99788.1};
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=15513918; DOI=10.1074/jbc.m409740200;
RA Liu J., Gluzman I.Y., Drew M.E., Goldberg D.E.;
RT "The role of Plasmodium falciparum food vacuole plasmepsins.";
RL J. Biol. Chem. 280:1432-1437(2005).
RN [3] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=16624575; DOI=10.1016/j.pep.2006.02.022;
RA Xiao H., Sinkovits A.F., Bryksa B.C., Ogawa M., Yada R.Y.;
RT "Recombinant expression and partial characterization of an active soluble
RT histo-aspartic protease from Plasmodium falciparum.";
RL Protein Expr. Purif. 49:88-94(2006).
RN [4] {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 [5] {ECO:0000305}
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PROTEOLYTIC CLEAVAGE,
RP AND MUTAGENESIS OF HIS-157; SER-160 AND ASP-337.
RX PubMed=18312598; DOI=10.1111/j.1742-4658.2008.06325.x;
RA Parr C.L., Tanaka T., Xiao H., Yada R.Y.;
RT "The catalytic significance of the proposed active site residues in
RT Plasmodium falciparum histoaspartic protease.";
RL FEBS J. 275:1698-1707(2008).
RN [6] {ECO:0000305}
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBUNIT.
RX PubMed=20435072; DOI=10.1016/j.molbiopara.2010.04.008;
RA Xiao H., Briere L.A., Dunn S.D., Yada R.Y.;
RT "Characterization of the monomer-dimer equilibrium of recombinant histo-
RT aspartic protease from Plasmodium falciparum.";
RL Mol. Biochem. Parasitol. 173:17-24(2010).
RN [7] {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 [8] {ECO:0007744|PDB:3FNS, ECO:0007744|PDB:3FNT, ECO:0007744|PDB:3FNU}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 120-451 IN APO FORM AND IN
RP COMPLEX WITH INHIBITOR, AND DISULFIDE BONDS.
RX PubMed=19285084; DOI=10.1016/j.jmb.2009.03.011;
RA Bhaumik P., Xiao H., Parr C.L., Kiso Y., Gustchina A., Yada R.Y.,
RA Wlodawer A.;
RT "Crystal structures of the histo-aspartic protease (HAP) from Plasmodium
RT falciparum.";
RL J. Mol. Biol. 388:520-540(2009).
CC -!- FUNCTION: During the asexual blood stage, catalyzes the cleavage of
CC denatured host hemoglobin (Hb) or globins (PubMed:16624575). Digestion
CC of host Hb is an essential step which provides the parasite with amino
CC acids for protein synthesis, and regulates osmolarity (Probable).
CC {ECO:0000269|PubMed:16624575, 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:16624575, ECO:0000269|PubMed:18312598,
CC ECO:0000269|PubMed:20435072};
CC -!- ACTIVITY REGULATION: Dimerization causes loss of catalytic activity
CC (PubMed:20435072). Inhibited by pepstatin A (PubMed:16624575).
CC Inhibited by Zn(2+) (PubMed:20435072). {ECO:0000269|PubMed:16624575,
CC ECO:0000269|PubMed:20435072}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.2 (PubMed:16624575). Activity decreases sharply at pH
CC above 6 (PubMed:16624575). Optimum pH is 5.5-7.5 (PubMed:18312598).
CC {ECO:0000269|PubMed:16624575, ECO:0000269|PubMed:18312598};
CC -!- SUBUNIT: Probable homodimer; in the zymogen form (Probable). Monomer;
CC in the active form (PubMed:20435072). Acidification disrupts
CC homodimerization (By similarity). Component of the hemozoin formation
CC complex (HFC) composed of falcipain 2, plasmepsins PMII, PMIII/HAP and
CC PMIV, heme detoxifying protein HDP and falcilysin FLN
CC (PubMed:23471987). The HFC complex is involved in hemoglobin
CC degradation and detoxification of heme in the food vacuole during the
CC asexual blood stage (PubMed:23471987). {ECO:0000250|UniProtKB:Q9Y006,
CC ECO:0000269|PubMed:20435072, ECO:0000269|PubMed:23471987,
CC ECO:0000305|PubMed:20435072}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass type II
CC membrane protein {ECO:0000305}. 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 (By
CC similarity). Proteolysis requires an acidic environment (By
CC similarity). Transprocessing may serve as an alternate activation
CC system (PubMed:18312598). {ECO:0000250|UniProtKB:P39898,
CC ECO:0000250|UniProtKB:Q9Y006, ECO:0000269|PubMed:18312598}.
CC -!- DISRUPTION PHENOTYPE: No growth defect (PubMed:15513918). However,
CC slight decrease in proliferation and slight increase in doubling time
CC during the asexual blood stage in an amino acid-limited medium
CC (PubMed:15513918). Triple knockout of PMI, PMII and PMIII causes a
CC slight decrease in proliferation during the asexual blood stage in an
CC amino acid-limited medium (PubMed:17581121). Quadruple knockout of PMI,
CC PMII, PMIII and PMIV causes a decrease in proliferation, an impaired
CC proliferation in an amino acid-limited medium, a reduced formation of
CC haemozoin and an abnormal accumulation of endosomal vesicles inside the
CC digestive vacuole (PubMed:17581121). {ECO:0000269|PubMed:15513918,
CC ECO:0000269|PubMed:17581121}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
CC -!- CAUTION: Unlike other plasmepsins, one of the two catalytic aspartates,
CC Asp-157, is replaced with histidine; however, the protein is catalytic
CC active (PubMed:16624575). Unlikely to act as a serine protease
CC (PubMed:18312598). His-157 may stabilizes the catalysis and Asp-337 may
CC act as both an acid and a base during catalysis.
CC {ECO:0000269|PubMed:16624575, ECO:0000269|PubMed:18312598,
CC ECO:0000305|PubMed:18312598}.
CC -!- CAUTION: It is unclear if PMIII 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; CZT99788.1; -; Genomic_DNA.
DR RefSeq; XP_001348251.1; XM_001348215.1.
DR PDB; 3FNS; X-ray; 2.50 A; A/B=120-451.
DR PDB; 3FNT; X-ray; 3.30 A; A=120-451.
DR PDB; 3FNU; X-ray; 3.00 A; A/B/C/D=120-451.
DR PDBsum; 3FNS; -.
DR PDBsum; 3FNT; -.
DR PDBsum; 3FNU; -.
DR AlphaFoldDB; Q8IM15; -.
DR SMR; Q8IM15; -.
DR STRING; 5833.PF14_0078; -.
DR DrugBank; DB11638; Artenimol.
DR MEROPS; A01.043; -.
DR SwissPalm; Q8IM15; -.
DR PRIDE; Q8IM15; -.
DR EnsemblProtists; CZT99788; CZT99788; PF3D7_1408100.
DR GeneID; 811660; -.
DR KEGG; pfa:PF3D7_1408100; -.
DR VEuPathDB; PlasmoDB:PF3D7_1408100; -.
DR HOGENOM; CLU_013253_3_2_1; -.
DR InParanoid; Q8IM15; -.
DR OMA; HKMPLIK; -.
DR PhylomeDB; Q8IM15; -.
DR EvolutionaryTrace; Q8IM15; -.
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: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; 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; 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..123
FT /evidence="ECO:0000250|UniProtKB:Q9Y006"
FT /id="PRO_0000453382"
FT CHAIN 124..451
FT /note="Plasmepsin III"
FT /id="PRO_0000453383"
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..451
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT DOMAIN 139..446
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT DISULFID 170..175
FT /evidence="ECO:0000269|PubMed:19285084,
FT ECO:0007744|PDB:3FNS, ECO:0007744|PDB:3FNT,
FT ECO:0007744|PDB:3FNU"
FT DISULFID 372..408
FT /evidence="ECO:0000269|PubMed:19285084,
FT ECO:0007744|PDB:3FNS, ECO:0007744|PDB:3FNT,
FT ECO:0007744|PDB:3FNU"
FT MUTAGEN 157
FT /note="H->A: Slight reduction in catalytic efficiency
FT towards a synthetic peptide."
FT /evidence="ECO:0000269|PubMed:18312598"
FT MUTAGEN 160
FT /note="S->A: Slight reduction in catalytic efficiency
FT towards a synthetic peptide."
FT /evidence="ECO:0000269|PubMed:18312598"
FT MUTAGEN 337
FT /note="D->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:18312598"
FT STRAND 127..136
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 138..145
FT /evidence="ECO:0007829|PDB:3FNS"
FT TURN 146..149
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 150..157
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 163..167
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 173..175
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 183..185
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 190..200
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 203..216
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 219..233
FT /evidence="ECO:0007829|PDB:3FNS"
FT TURN 235..240
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 245..248
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 252..254
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 255..257
FT /evidence="ECO:0007829|PDB:3FNU"
FT HELIX 262..268
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 271..280
FT /evidence="ECO:0007829|PDB:3FNS"
FT TURN 283..286
FT /evidence="ECO:0007829|PDB:3FNU"
FT STRAND 289..295
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 298..300
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 301..303
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 306..324
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 327..336
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 343..345
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 347..359
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 360..362
FT /evidence="ECO:0007829|PDB:3FNT"
FT STRAND 365..371
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 388..391
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 393..396
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 397..404
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 406..410
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 412..414
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 421..424
FT /evidence="ECO:0007829|PDB:3FNS"
FT HELIX 426..431
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 432..437
FT /evidence="ECO:0007829|PDB:3FNS"
FT TURN 438..441
FT /evidence="ECO:0007829|PDB:3FNS"
FT STRAND 442..448
FT /evidence="ECO:0007829|PDB:3FNS"
SQ SEQUENCE 451 AA; 51693 MW; D9ED8C4A066B2154 CRC64;
MNLTIKEEDF TNTFMKNEES FNTFRVTKVK RWNAKRLFKI LFVTVFIVLA GGFSYYIFEN
FVFQKNRKIN HIIKTSKYST VGFNIENSYD RLMKTIKEHK LKNYIKESVK LFNKGLTKKS
YLGSEFDNVE LKDLANVLSF GEAKLGDNGQ KFNFLFHTAS SNVWVPSIKC TSESCESKNH
YDSSKSKTYE KDDTPVKLTS KAGTISGIFS KDLVTIGKLS VPYKFIEMTE IVGFEPFYSE
SDVDGVFGLG WKDLSIGSID PYIVELKTQN KIEQAVYSIY LPPENKNKGY LTIGGIEERF
FDGPLNYEKL NHDLMWQVDL DVHFGNVSSK KANVILDSAT SVITVPTEFF NQFVESASVF
KVPFLSLYVT TCGNTKLPTL EYRSPNKVYT LEPKQYLEPL ENIFSALCML NIVPIDLEKN
TFVLGDPFMR KYFTVYDYDN HTVGFALAKN L
