PLM3_PLAFX
ID PLM3_PLAFX Reviewed; 451 AA.
AC Q9Y006; A0A0L7K5R8;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Plasmepsin III {ECO:0000305};
DE EC=3.4.23.39 {ECO:0000269|PubMed:11782538};
DE AltName: Full=Histo-aspartic protease {ECO:0000303|PubMed:10214936};
DE AltName: Full=Plasmepsin 3 {ECO:0000305};
DE Flags: Precursor;
GN Name=PMIII {ECO:0000305}; Synonyms=HAP {ECO:0000303|PubMed:10214936};
GN ORFNames=PFHG_00466 {ECO:0000312|EMBL:KOB58718.1};
OS Plasmodium falciparum (isolate HB3).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=137071 {ECO:0000312|Proteomes:UP000054289};
RN [1] {ECO:0000312|EMBL:CAB40630.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND DEVELOPMENTAL STAGE.
RX PubMed=10214936; DOI=10.1016/s0014-5793(99)00276-8;
RA Berry C., Humphreys M.J., Matharu P., Granger R., Horrocks P., Moon R.P.,
RA Certa U., Ridley R.G., Bur D., Kay J.;
RT "A distinct member of the aspartic proteinase gene family from the human
RT malaria parasite Plasmodium falciparum.";
RL FEBS Lett. 447:149-154(1999).
RN [2] {ECO:0000312|EMBL:AAW71454.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=7G8 {ECO:0000312|EMBL:AAW71455.1}, D6 {ECO:0000312|EMBL:AAW71456.1},
RC HB3 {ECO:0000312|EMBL:AAW71457.1}, MUZ12 {ECO:0000312|EMBL:AAW71458.1}, and
RC W2 {ECO:0000312|EMBL:AAW71454.1};
RX PubMed=16784823; DOI=10.1016/j.gene.2006.02.029;
RA Barry A.E., Leliwa-Sytek A., Man K., Kasper J.M., Hartl D.L., Day K.P.;
RT "Variable SNP density in aspartyl-protease genes of the malaria parasite
RT Plasmodium falciparum.";
RL Gene 376:163-173(2006).
RN [3] {ECO:0000312|Proteomes:UP000054289}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=HB3 {ECO:0000312|Proteomes:UP000054289};
RG The Broad Institute Genome Sequencing Platform;
RA Volkman S.K., Neafsey D.E., Dash A.P., Chitnis C.E., Hartl D.L.,
RA Young S.K., Zeng Q., Koehrsen M., Alvarado L., Berlin A., Borenstein D.,
RA Chapman S.B., Chen Z., Engels R., Freedman E., Gellesch M., Goldberg J.,
RA Griggs A., Gujja S., Heilman E.R., Heiman D.I., Howarth C., Jen D.,
RA Larson L., Mehta T., Neiman D., Park D., Pearson M., Roberts A., Saif S.,
RA Shea T., Shenoy N., Sisk P., Stolte C., Sykes S., Walk T., White J.,
RA Yandava C., Haas B., Henn M.R., Nusbaum C., Birren B.;
RT "Annotation of Plasmodium falciparum HB3.";
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBUNIT, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=11782538; DOI=10.1073/pnas.022630099;
RA Banerjee R., Liu J., Beatty W., Pelosof L., Klemba M., Goldberg D.E.;
RT "Four plasmepsins are active in the Plasmodium falciparum food vacuole,
RT including a protease with an active-site histidine.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:990-995(2002).
RN [5] {ECO:0000305}
RP DEVELOPMENTAL STAGE, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=12850260; DOI=10.1016/s0166-6851(03)00119-1;
RA Banerjee R., Francis S.E., Goldberg D.E.;
RT "Food vacuole plasmepsins are processed at a conserved site by an acidic
RT convertase activity in Plasmodium falciparum.";
RL Mol. Biochem. Parasitol. 129:157-165(2003).
RN [6] {ECO:0007744|PDB:3QVC, ECO:0007744|PDB:3QVI}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN APO FORM AND IN COMPLEX WITH
RP INHIBITOR, AND DISULFIDE BONDS.
RX PubMed=21928835; DOI=10.1021/bi201118z;
RA Bhaumik P., Xiao H., Hidaka K., Gustchina A., Kiso Y., Yada R.Y.,
RA Wlodawer A.;
RT "Structural insights into the activation and inhibition of histo-aspartic
RT protease from Plasmodium falciparum.";
RL Biochemistry 50:8862-8879(2011).
RN [7] {ECO:0007744|PDB:6KUB, ECO:0007744|PDB:6KUC, ECO:0007744|PDB:6KUD}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 77-451, SUBUNIT, PROTEOLYTIC
RP CLEAVAGE, AND DISULFIDE BONDS.
RX PubMed=32385863; DOI=10.1111/febs.15363;
RA Rathore I., Mishra V., Patel C., Xiao H., Gustchina A., Wlodawer A.,
RA Yada R.Y., Bhaumik P.;
RT "Activation mechanism of plasmepsins, pepsin-like aspartic proteases from
RT Plasmodium, follows a unique trans-activation pathway.";
RL FEBS J. 288:678-698(2021).
CC -!- FUNCTION: During the asexual blood stage, catalyzes the cleavage of
CC denatured host hemoglobin (Hb) or globins (PubMed:11782538). 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:11782538, 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:11782538};
CC -!- ACTIVITY REGULATION: Dimerization causes loss of catalytic activity (By
CC similarity). Inhibited by pepstatin A (PubMed:11782538).
CC {ECO:0000250|UniProtKB:Q8IM15, ECO:0000269|PubMed:11782538}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.7. {ECO:0000269|PubMed:11782538};
CC -!- SUBUNIT: Probable homodimer; in the zymogen form (PubMed:32385863).
CC Monomer; in the active form (PubMed:11782538, PubMed:32385863).
CC Acidification disrupts homodimerization (PubMed:32385863). Component of
CC the hemozoin formation complex (HFC) composed of falcipain 2,
CC plasmepsins PMII, PMIII/HAP and PMIV, heme detoxifying protein HDP and
CC falcilysin FLN (By similarity). The HFC complex is involved in
CC hemoglobin degradation and detoxification of heme in the food vacuole
CC during the asexual blood stage (By similarity).
CC {ECO:0000250|UniProtKB:Q8IM15, ECO:0000269|PubMed:11782538,
CC ECO:0000269|PubMed:32385863}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass type II
CC membrane protein {ECO:0000305}. Vacuole lumen
CC {ECO:0000269|PubMed:11782538}. Note=In trophozoites, localizes to the
CC digestive (or food) vacuole, an acidic vacuole where host hemoglobin is
CC digested. {ECO:0000269|PubMed:11782538}.
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:10214936,
CC ECO:0000269|PubMed:11782538, ECO:0000269|PubMed:12850260}.
CC -!- PTM: Proteolytically cleaved into the soluble active mature form by
CC cysteine proteases in the digestive vacuole of trophozoites
CC (PubMed:12850260). Proteolysis requires an acidic environment (By
CC similarity). Transprocessing may serve as an alternate activation
CC system (Probable). {ECO:0000250|UniProtKB:P39898,
CC ECO:0000269|PubMed:12850260, ECO:0000305|PubMed:32385863}.
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:11782538). Unlikely to act as a serine protease (By
CC similarity). His-157 may stabilizes the catalysis and Asp-337 may act
CC as both an acid and a base during catalysis (By similarity).
CC {ECO:0000250|UniProtKB:Q8IM15, ECO:0000269|PubMed:11782538}.
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; AY878730; AAW71454.1; -; Genomic_DNA.
DR EMBL; AY878731; AAW71455.1; -; Genomic_DNA.
DR EMBL; AY878732; AAW71456.1; -; Genomic_DNA.
DR EMBL; AY878733; AAW71457.1; -; Genomic_DNA.
DR EMBL; AY878734; AAW71458.1; -; Genomic_DNA.
DR EMBL; AJ009990; CAB40630.1; -; Genomic_DNA.
DR EMBL; CH671923; KOB58718.1; -; Genomic_DNA.
DR PDB; 3QVC; X-ray; 2.10 A; A=1-451.
DR PDB; 3QVI; X-ray; 2.50 A; A/B/C/D=1-451.
DR PDB; 6KUB; X-ray; 2.00 A; A=77-451.
DR PDB; 6KUC; X-ray; 2.50 A; A=77-451.
DR PDB; 6KUD; X-ray; 2.90 A; A=77-451.
DR PDBsum; 3QVC; -.
DR PDBsum; 3QVI; -.
DR PDBsum; 6KUB; -.
DR PDBsum; 6KUC; -.
DR PDBsum; 6KUD; -.
DR SMR; Q9Y006; -.
DR BindingDB; Q9Y006; -.
DR ChEMBL; CHEMBL6075; -.
DR MEROPS; A01.043; -.
DR EnsemblProtists; KOB58718; KOB58718; PFHG_00466.
DR VEuPathDB; PlasmoDB:PF3D7_1408100; -.
DR VEuPathDB; PlasmoDB:Pf7G8-2_000483300; -.
DR VEuPathDB; PlasmoDB:Pf7G8_140013500; -.
DR VEuPathDB; PlasmoDB:PfCD01_140013800; -.
DR VEuPathDB; PlasmoDB:PfDd2_140012700; -.
DR VEuPathDB; PlasmoDB:PfGA01_140013800; -.
DR VEuPathDB; PlasmoDB:PfGB4_140014300; -.
DR VEuPathDB; PlasmoDB:PfGN01_140013400; -.
DR VEuPathDB; PlasmoDB:PfHB3_140014000; -.
DR VEuPathDB; PlasmoDB:PfIT_140014700; -.
DR VEuPathDB; PlasmoDB:PfKE01_140013400; -.
DR VEuPathDB; PlasmoDB:PfKH01_140013700; -.
DR VEuPathDB; PlasmoDB:PfKH02_140014000; -.
DR VEuPathDB; PlasmoDB:PfML01_140013600; -.
DR VEuPathDB; PlasmoDB:PfNF135_140013600; -.
DR VEuPathDB; PlasmoDB:PfNF166_140012300; -.
DR VEuPathDB; PlasmoDB:PfNF54_140013100; -.
DR VEuPathDB; PlasmoDB:PfSD01_140011600; -.
DR VEuPathDB; PlasmoDB:PfSN01_140015500; -.
DR VEuPathDB; PlasmoDB:PfTG01_140013500; -.
DR OMA; HKMPLIK; -.
DR BioCyc; MetaCyc:MON-15377; -.
DR EvolutionaryTrace; Q9Y006; -.
DR Proteomes; UP000054289; Unassembled WGS sequence.
DR GO; GO:0020020; C:food vacuole; IDA:UniProtKB.
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; IEA:UniProtKB-KW.
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:0000269|PubMed:12850260"
FT /id="PRO_0000453380"
FT CHAIN 124..451
FT /note="Plasmepsin III"
FT /id="PRO_0000453381"
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 ACT_SITE 337
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT DISULFID 170..175
FT /evidence="ECO:0000269|PubMed:21928835,
FT ECO:0000269|PubMed:32385863, ECO:0007744|PDB:3QVC,
FT ECO:0007744|PDB:3QVI, ECO:0007744|PDB:6KUB,
FT ECO:0007744|PDB:6KUC, ECO:0007744|PDB:6KUD"
FT DISULFID 372..408
FT /evidence="ECO:0000269|PubMed:21928835,
FT ECO:0000269|PubMed:32385863, ECO:0007744|PDB:3QVC,
FT ECO:0007744|PDB:3QVI, ECO:0007744|PDB:6KUB,
FT ECO:0007744|PDB:6KUC, ECO:0007744|PDB:6KUD"
FT CONFLICT 451
FT /note="L -> F (in Ref. 3; KOB58718)"
FT /evidence="ECO:0000305"
FT STRAND 77..86
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 88..98
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 102..113
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 131..134
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 137..145
FT /evidence="ECO:0007829|PDB:6KUB"
FT TURN 146..149
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 150..160
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 163..167
FT /evidence="ECO:0007829|PDB:6KUB"
FT TURN 174..177
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 183..185
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 190..199
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 201..216
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 219..233
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 237..240
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 245..248
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 250..252
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 254..257
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 262..268
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 271..280
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 285..287
FT /evidence="ECO:0007829|PDB:3QVI"
FT STRAND 288..295
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 298..300
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 301..309
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 315..324
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 327..336
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 340..345
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 347..354
FT /evidence="ECO:0007829|PDB:6KUB"
FT TURN 355..358
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 368..371
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 388..391
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 393..396
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 397..399
FT /evidence="ECO:0007829|PDB:6KUB"
FT TURN 401..403
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 407..410
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 412..414
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 421..424
FT /evidence="ECO:0007829|PDB:6KUB"
FT HELIX 426..431
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 432..437
FT /evidence="ECO:0007829|PDB:6KUB"
FT TURN 438..441
FT /evidence="ECO:0007829|PDB:6KUB"
FT STRAND 442..448
FT /evidence="ECO:0007829|PDB:6KUB"
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
