PLM2_PLAF7
ID PLM2_PLAF7 Reviewed; 453 AA.
AC Q8I6V3;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Plasmepsin II {ECO:0000303|PubMed:14709539};
DE EC=3.4.23.39 {ECO:0000269|PubMed:29943906};
DE AltName: Full=Plasmepsin 2 {ECO:0000305};
DE Flags: Precursor;
GN Name=PMII {ECO:0000303|PubMed:29943906};
GN ORFNames=PF3D7_1408000 {ECO:0000312|EMBL:CZT99787.1};
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 SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=14709539; DOI=10.1083/jcb200307147;
RA Klemba M., Beatty W., Gluzman I., Goldberg D.E.;
RT "Trafficking of plasmepsin II to the food vacuole of the malaria parasite
RT Plasmodium falciparum.";
RL J. Cell Biol. 164:47-56(2004).
RN [3] {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 [4] {ECO:0000305}
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=18308731; DOI=10.1074/jbc.m708949200;
RA Drew M.E., Banerjee R., Uffman E.W., Gilbertson S., Rosenthal P.J.,
RA Goldberg D.E.;
RT "Plasmodium food vacuole plasmepsins are activated by falcipains.";
RL J. Biol. Chem. 283:12870-12876(2008).
RN [5] {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 [6] {ECO:0007744|PDB:5YIA, ECO:0007744|PDB:5YIB, ECO:0007744|PDB:5YIC, ECO:0007744|PDB:5YID, ECO:0007744|PDB:5YIE}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 126-453 IN COMPLEX WITH
RP INHIBITOR, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND DISULFIDE
RP BONDS.
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).
CC -!- FUNCTION: During the asexual blood stage, participates in initial
CC cleavage of native host hemoglobin (Hb) resulting in Hb denaturation
CC (PubMed:29943906). May cleave preferentially denatured hemoglobin that
CC has been cleaved by PMI (By similarity). Digestion of host Hb is an
CC essential step which provides the parasite with amino acids for protein
CC synthesis, and regulates osmolarity (Probable).
CC {ECO:0000250|UniProtKB:P46925, ECO:0000269|PubMed:29943906,
CC 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 pepstatin A (PubMed:29943906).
CC Inhibited by KNI derived compounds (KNI-10742, 10743, 10395, 10333, and
CC 10343) (PubMed:29943906). {ECO:0000269|PubMed:29943906}.
CC -!- SUBUNIT: Component of the hemozoin formation complex (HFC) composed of
CC falcipain 2, plasmepsins PMII, PMIII/HAP and PMIV, heme detoxifying
CC protein HDP and falcilysin FLN (PubMed:23471987). The HFC complex is
CC involved in hemoglobin degradation and detoxification of heme in the
CC food vacuole during the asexual blood stage (PubMed:23471987).
CC {ECO:0000269|PubMed:23471987}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:14709539}; Single-
CC pass type II membrane protein {ECO:0000255}. Vacuole lumen
CC {ECO:0000269|PubMed:14709539, ECO:0000269|PubMed:23471987}. Vacuole
CC membrane {ECO:0000269|PubMed:14709539}. Note=At the beginning of the
CC asexual blood stage, the transmembrane zymogen is transported to the
CC cytostome, an endocytic structure spanning the parasite cell membrane
CC and the parasitophorous vacuole membrane where host proteins such as
CC hemoglobin are endocytosed (PubMed:14709539). Following endocytosis,
CC localizes to the cytostome vacuole membrane to be then delivered to the
CC digestive (or food) vacuole where it is cleaved into the soluble and
CC active enzyme (PubMed:14709539). In trophozoites, localizes to the
CC digestive vacuole, an acidic vacuole where host hemoglobin is digested
CC (PubMed:14709539). {ECO:0000269|PubMed:14709539}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the asexual blood stage including
CC in trophozoites (at protein level). {ECO:0000269|PubMed:14709539,
CC ECO:0000269|PubMed:23471987}.
CC -!- PTM: Not N-glycosylated. {ECO:0000250|UniProtKB:P46925}.
CC -!- PTM: Proteolytically cleaved into the soluble active mature form in the
CC digestive vacuole by cysteine protease falcipains; the process begins
CC at the early ring stage (PubMed:14709539, PubMed:18308731). Proteolysis
CC requires an acidic environment (PubMed:14709539, PubMed:18308731). In
CC absence of falcipains, autoprocessing may serve as an alternate
CC activation system (PubMed:18308731). {ECO:0000269|PubMed:14709539,
CC ECO:0000269|PubMed:18308731}.
CC -!- DISRUPTION PHENOTYPE: Slight decrease in proliferation and slight
CC increase in doubling time during the asexual blood stage.
CC {ECO:0000269|PubMed:15513918}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family.
CC {ECO:0000255|RuleBase:RU000454}.
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DR EMBL; LN999946; CZT99787.1; -; Genomic_DNA.
DR RefSeq; XP_001348250.1; XM_001348214.1.
DR PDB; 5YIA; X-ray; 2.00 A; A=126-453.
DR PDB; 5YIB; X-ray; 2.15 A; A=126-453.
DR PDB; 5YIC; X-ray; 1.90 A; A=126-453.
DR PDB; 5YID; X-ray; 2.10 A; A=127-453.
DR PDB; 5YIE; X-ray; 2.10 A; A=127-453.
DR PDBsum; 5YIA; -.
DR PDBsum; 5YIB; -.
DR PDBsum; 5YIC; -.
DR PDBsum; 5YID; -.
DR PDBsum; 5YIE; -.
DR AlphaFoldDB; Q8I6V3; -.
DR SMR; Q8I6V3; -.
DR STRING; 5833.PF14_0077; -.
DR MEROPS; A01.023; -.
DR SwissPalm; Q8I6V3; -.
DR PRIDE; Q8I6V3; -.
DR EnsemblProtists; CZT99787; CZT99787; PF3D7_1408000.
DR GeneID; 811659; -.
DR KEGG; pfa:PF3D7_1408000; -.
DR VEuPathDB; PlasmoDB:PF3D7_1408000; -.
DR HOGENOM; CLU_013253_3_2_1; -.
DR InParanoid; Q8I6V3; -.
DR OMA; DKSHYTG; -.
DR PhylomeDB; Q8I6V3; -.
DR BRENDA; 3.4.23.39; 4889.
DR Proteomes; UP000001450; Chromosome 14.
DR GO; GO:0031910; C:cytostome; IDA:UniProtKB.
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:0005774; C:vacuolar membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0042540; P:hemoglobin catabolic process; TAS: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.
FT PROPEP 1..124
FT /evidence="ECO:0000269|PubMed:18308731"
FT /id="PRO_0000453261"
FT CHAIN 125..453
FT /note="Plasmepsin II"
FT /id="PRO_0000453262"
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..453
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT DOMAIN 140..447
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 158
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 338
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT DISULFID 171..176
FT /evidence="ECO:0000269|PubMed:29943906,
FT ECO:0007744|PDB:5YIA, ECO:0007744|PDB:5YIB"
FT DISULFID 373..409
FT /evidence="ECO:0000269|PubMed:29943906,
FT ECO:0007744|PDB:5YIA, ECO:0007744|PDB:5YIB"
FT STRAND 128..135
FT /evidence="ECO:0007829|PDB:5YIC"
FT TURN 136..138
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 139..146
FT /evidence="ECO:0007829|PDB:5YIC"
FT TURN 147..150
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 151..158
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 164..168
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 174..178
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 184..186
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 191..201
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 204..217
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 220..231
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 233..235
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 238..241
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 246..249
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 253..255
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 256..258
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 263..269
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 272..281
FT /evidence="ECO:0007829|PDB:5YIC"
FT TURN 285..287
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 290..296
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 299..301
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 302..310
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 312..316
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 318..325
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 328..337
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 343..346
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 348..355
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 369..372
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 381..384
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 389..392
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 394..397
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 398..400
FT /evidence="ECO:0007829|PDB:5YIC"
FT TURN 402..404
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 408..411
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 413..415
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 422..425
FT /evidence="ECO:0007829|PDB:5YIC"
FT HELIX 427..432
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 433..438
FT /evidence="ECO:0007829|PDB:5YIC"
FT TURN 439..442
FT /evidence="ECO:0007829|PDB:5YIC"
FT STRAND 443..449
FT /evidence="ECO:0007829|PDB:5YIC"
SQ SEQUENCE 453 AA; 51481 MW; 0D78A8B9600C80B5 CRC64;
MDITVREHDF KHGFIKSNST FDGLNIDNSK NKKKIQKGFQ ILYVLLFCSV MCGLFYYVYE
NVWLQRDNEM NEILKNSEHL TIGFKVENAH DRILKTIKTH KLKNYIKESV NFLNSGLTKT
NYLGSSNDNI ELVDFQNIMF YGDAEVGDNQ QPFTFILDTG SANLWVPSVK CTTAGCLTKH
LYDSSKSRTY EKDGTKVEMN YVSGTVSGFF SKDLVTVGNL SLPYKFIEVI DTNGFEPTYT
ASTFDGILGL GWKDLSIGSV DPIVVELKNQ NKIENALFTF YLPVHDKHTG FLTIGGIEER
FYEGPLTYEK LNHDLYWQIT LDAHVGNIML EKANCIVDSG TSAITVPTDF LNKMLQNLDV
IKVPFLPFYV TLCNNSKLPT FEFTSENGKY TLEPEYYLQH IEDVGPGLCM LNIIGLDFPV
PTFILGDPFM RKYFTVFDYD NQSVGIALAK KNL
