PLM5_PLAF7
ID PLM5_PLAF7 Reviewed; 590 AA.
AC Q8I6Z5;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 25-MAY-2022, entry version 120.
DE RecName: Full=Plasmepsin V {ECO:0000303|PubMed:20130643};
DE Short=PfPMV {ECO:0000303|PubMed:24983235};
DE EC=3.4.23.- {ECO:0000269|PubMed:20130643, ECO:0000269|PubMed:20130644, ECO:0000269|PubMed:23387285, ECO:0000269|PubMed:24983235, ECO:0000269|PubMed:25447707, ECO:0000269|PubMed:25986559, ECO:0000269|PubMed:26214367};
DE AltName: Full=Plasmepsin 5 {ECO:0000303|PubMed:20117149};
DE Flags: Precursor;
GN Name=PMV {ECO:0000303|PubMed:20130643};
GN ORFNames=PF3D7_1323500 {ECO:0000312|EMBL:CAD52383.1};
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:0000312|Proteomes:UP000001450}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=3D7 {ECO:0000312|Proteomes:UP000001450};
RX PubMed=12368867; DOI=10.1038/nature01095;
RA Hall N., Pain A., Berriman M., Churcher C.M., Harris B., Harris D.,
RA Mungall K.L., Bowman S., Atkin R., Baker S., Barron A., Brooks K.,
RA Buckee C.O., Burrows C., Cherevach I., Chillingworth C., Chillingworth T.,
RA Christodoulou Z., Clark L., Clark R., Corton C., Cronin A., Davies R.M.,
RA Davis P., Dear P., Dearden F., Doggett J., Feltwell T., Goble A.,
RA Goodhead I., Gwilliam R., Hamlin N., Hance Z., Harper D., Hauser H.,
RA Hornsby T., Holroyd S., Horrocks P., Humphray S., Jagels K., James K.D.,
RA Johnson D., Kerhornou A., Knights A., Konfortov B., Kyes S., Larke N.,
RA Lawson D., Lennard N., Line A., Maddison M., Mclean J., Mooney P.,
RA Moule S., Murphy L., Oliver K., Ormond D., Price C., Quail M.A.,
RA Rabbinowitsch E., Rajandream M.A., Rutter S., Rutherford K.M., Sanders M.,
RA Simmonds M., Seeger K., Sharp S., Smith R., Squares R., Squares S.,
RA Stevens K., Taylor K., Tivey A., Unwin L., Whitehead S., Woodward J.R.,
RA Sulston J.E., Craig A., Newbold C., Barrell B.G.;
RT "Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13.";
RL Nature 419:527-531(2002).
RN [3] {ECO:0000305}
RP SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=20117149; DOI=10.1016/j.molbiopara.2010.01.003;
RA Osborne A.R., Speicher K.D., Tamez P.A., Bhattacharjee S., Speicher D.W.,
RA Haldar K.;
RT "The host targeting motif in exported Plasmodium proteins is cleaved in the
RT parasite endoplasmic reticulum.";
RL Mol. Biochem. Parasitol. 171:25-31(2010).
RN [4] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP ASP-118; ASP-365 AND PHE-370.
RX PubMed=20130643; DOI=10.1038/nature08728;
RA Boddey J.A., Hodder A.N., Guenther S., Gilson P.R., Patsiouras H.,
RA Kapp E.A., Pearce J.A., de Koning-Ward T.F., Simpson R.J., Crabb B.S.,
RA Cowman A.F.;
RT "An aspartyl protease directs malaria effector proteins to the host cell.";
RL Nature 463:627-631(2010).
RN [5] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS
RP OF ASP-118.
RX PubMed=20130644; DOI=10.1038/nature08726;
RA Russo I., Babbitt S., Muralidharan V., Butler T., Oksman A., Goldberg D.E.;
RT "Plasmepsin V licenses Plasmodium proteins for export into the host
RT erythrocyte.";
RL Nature 463:632-636(2010).
RN [6] {ECO:0000305}
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23387285; DOI=10.1111/tra.12053;
RA Boddey J.A., Carvalho T.G., Hodder A.N., Sargeant T.J., Sleebs B.E.,
RA Marapana D., Lopaticki S., Nebl T., Cowman A.F.;
RT "Role of plasmepsin V in export of diverse protein families from the
RT Plasmodium falciparum exportome.";
RL Traffic 14:532-550(2013).
RN [7] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=25447707; DOI=10.1016/j.molbiopara.2014.10.004;
RA Xiao H., Bryksa B.C., Bhaumik P., Gustchina A., Kiso Y., Yao S.Q.,
RA Wlodawer A., Yada R.Y.;
RT "The zymogen of plasmepsin V from Plasmodium falciparum is enzymatically
RT active.";
RL Mol. Biochem. Parasitol. 197:56-63(2014).
RN [8] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP ASP-118 AND ASP-365.
RX PubMed=24983235; DOI=10.1371/journal.pbio.1001897;
RA Sleebs B.E., Lopaticki S., Marapana D.S., O'Neill M.T., Rajasekaran P.,
RA Gazdik M., Guenther S., Whitehead L.W., Lowes K.N., Barfod L., Hviid L.,
RA Shaw P.J., Hodder A.N., Smith B.J., Cowman A.F., Boddey J.A.;
RT "Inhibition of Plasmepsin V activity demonstrates its essential role in
RT protein export, PfEMP1 display, and survival of malaria parasites.";
RL PLoS Biol. 12:e1001897-e1001897(2014).
RN [9] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=25986559; DOI=10.1016/j.molbiopara.2015.05.004;
RA Boonyalai N., Sittikul P., Yuvaniyama J.;
RT "Plasmodium falciparum Plasmepsin V (PfPMV): Insights into recombinant
RT expression, substrate specificity and active site structure.";
RL Mol. Biochem. Parasitol. 201:5-15(2015).
RN [10] {ECO:0000305}
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=26214367; DOI=10.1038/nsmb.3061;
RA Hodder A.N., Sleebs B.E., Czabotar P.E., Gazdik M., Xu Y., O'Neill M.T.,
RA Lopaticki S., Nebl T., Triglia T., Smith B.J., Lowes K., Boddey J.A.,
RA Cowman A.F.;
RT "Structural basis for plasmepsin V inhibition that blocks export of malaria
RT proteins to human erythrocytes.";
RL Nat. Struct. Mol. Biol. 22:590-596(2015).
RN [11] {ECO:0000305}
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=25849462; DOI=10.1371/journal.pone.0121786;
RA Tarr S.J., Osborne A.R.;
RT "Experimental determination of the membrane topology of the Plasmodium
RT protease Plasmepsin V.";
RL PLoS ONE 10:e0121786-e0121786(2015).
RN [12] {ECO:0000305}
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH SPC25, INTERACTION WITH THE
RP SEC61 CHANNEL-FORMING TRANSLOCON COMPLEX, SUBCELLULAR LOCATION, AND
RP DEVELOPMENTAL STAGE.
RX PubMed=30127496; DOI=10.1038/s41564-018-0219-2;
RA Marapana D.S., Dagley L.F., Sandow J.J., Nebl T., Triglia T., Pasternak M.,
RA Dickerman B.K., Crabb B.S., Gilson P.R., Webb A.I., Boddey J.A.,
RA Cowman A.F.;
RT "Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic
RT reticulum translocation interactome for export to the erythrocyte.";
RL Nat. Microbiol. 3:1010-1022(2018).
RN [13] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF 133-ASP--THR-590.
RX PubMed=30517136; DOI=10.1371/journal.pone.0207621;
RA Boonyalai N., Collins C.R., Hackett F., Withers-Martinez C., Blackman M.J.;
RT "Essentiality of Plasmodium falciparum plasmepsin V.";
RL PLoS ONE 13:e0207621-e0207621(2018).
CC -!- FUNCTION: During the asexual blood stage, plays an essential role in
CC the export of several proteins into the host erythrocytes by cleaving
CC the pentameric localization motif RxLxE/Q/D (termed Plasmodium export
CC element (PEXEL)) located downstream of the N-terminal secretory signal
CC sequence (PubMed:20130643, PubMed:20130644, PubMed:24983235,
CC PubMed:30127496, PubMed:30517136). Specifically, cleaves after the
CC leucine residue in the RxLxE/Q/D (or RxLxxE) motif of exported proteins
CC including RESA, EMP2, EMP3, KAHRP, RIF/Rifin and STEVOR
CC (PubMed:20130643, PubMed:20130644, PubMed:23387285, PubMed:25447707,
CC PubMed:25986559, PubMed:24983235). Also, by regulating protein export,
CC plays an essential role in gametocyte development and thus, parasite
CC transmission to the mosquito vector (By similarity).
CC {ECO:0000250|UniProtKB:W7JPD9, ECO:0000269|PubMed:20130643,
CC ECO:0000269|PubMed:20130644, ECO:0000269|PubMed:23387285,
CC ECO:0000269|PubMed:24983235, ECO:0000269|PubMed:25447707,
CC ECO:0000269|PubMed:25986559, ECO:0000269|PubMed:30127496,
CC ECO:0000269|PubMed:30517136}.
CC -!- ACTIVITY REGULATION: Inhibited by peptidomimetic inhibitor WEHI-842
CC (PubMed:26214367). Inhibited by Cu(2+) and Hg(2+) (PubMed:25447707).
CC {ECO:0000269|PubMed:25447707, ECO:0000269|PubMed:26214367}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is between 5.5 and 7. {ECO:0000269|PubMed:25447707,
CC ECO:0000269|PubMed:25986559};
CC -!- SUBUNIT: Component of a complex composed of SPC25 and PMV; the
CC interaction is mediated via the transmembrane domains
CC (PubMed:30127496). The complex interacts with the SEC61 channel-forming
CC translocon complex and is involved in the recognition and import of
CC PEXEL motif-containing proteins into the ER for subsequent export
CC (PubMed:30127496). {ECO:0000269|PubMed:30127496}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:20117149, ECO:0000269|PubMed:20130643,
CC ECO:0000269|PubMed:20130644, ECO:0000269|PubMed:24983235,
CC ECO:0000269|PubMed:25849462, ECO:0000269|PubMed:30127496}; Single-pass
CC type I membrane protein {ECO:0000269|PubMed:25849462}. Note=During
CC gametogenesis, localizes to the perinuclear ER in stage I-II
CC gametocytes, and relocalizes towards the cell periphery as the ER
CC redistributes in the cell in stage III-IV gametocytes (By similarity).
CC Partially colocalizes with SPC25 in the endoplasmic reticulum
CC (PubMed:30127496). {ECO:0000250|UniProtKB:W7JPD9,
CC ECO:0000269|PubMed:30127496}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the asexual blood stage;
CC expression is low at the ring stage and then increases through the
CC trophozoite and schizont stages (at protein level).
CC {ECO:0000269|PubMed:20117149, ECO:0000269|PubMed:30127496}.
CC -!- DOMAIN: The transmembrane domain is essential for localization to the
CC endoplasmic reticulum. {ECO:0000269|PubMed:20130644}.
CC -!- PTM: It is not clear if the zymogen has a cleavable propeptide
CC (PubMed:25447707). In vitro, appears to be cleaved between Asn-80 and
CC Ala-81 (PubMed:25447707). Cleavage of the putative propeptide is
CC dispensable for catalytic activity (PubMed:25447707, PubMed:25986559).
CC {ECO:0000269|PubMed:25447707, ECO:0000269|PubMed:25986559}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family.
CC {ECO:0000255|RuleBase:RU000454}.
CC -!- CAUTION: It is unclear if PMV 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; AL844509; CAD52383.1; -; Genomic_DNA.
DR RefSeq; XP_001349975.1; XM_001349939.1.
DR AlphaFoldDB; Q8I6Z5; -.
DR SMR; Q8I6Z5; -.
DR STRING; 5833.PF13_0133; -.
DR BindingDB; Q8I6Z5; -.
DR ChEMBL; CHEMBL3559649; -.
DR GuidetoPHARMACOLOGY; 3106; -.
DR MEROPS; A01.075; -.
DR TCDB; 8.A.32.1.6; the Beta-amyloid cleaving enzyme (bace1) family.
DR SwissPalm; Q8I6Z5; -.
DR PRIDE; Q8I6Z5; -.
DR EnsemblProtists; CAD52383; CAD52383; PF3D7_1323500.
DR GeneID; 814104; -.
DR KEGG; pfa:PF3D7_1323500; -.
DR VEuPathDB; PlasmoDB:PF3D7_1323500; -.
DR HOGENOM; CLU_526282_0_0_1; -.
DR InParanoid; Q8I6Z5; -.
DR OMA; CEGSQIS; -.
DR PhylomeDB; Q8I6Z5; -.
DR BRENDA; 3.4.23.B19; 4889.
DR Reactome; R-PFA-2132295; MHC class II antigen presentation.
DR Reactome; R-PFA-6798695; Neutrophil degranulation.
DR PHI-base; PHI:8625; -.
DR Proteomes; UP000001450; Chromosome 13.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:GeneDB.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:GeneDB.
DR GO; GO:0031227; C:intrinsic component of endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0032527; P:protein exit from endoplasmic reticulum; IMP:UniProtKB.
DR GO; GO:0016485; P:protein processing; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:GeneDB.
DR CDD; cd06096; Plasmepsin_5; 1.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase_A1.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR033121; PEPTIDASE_A1.
DR InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR InterPro; IPR033866; Plasmepsin_5.
DR InterPro; IPR032861; TAXi_N.
DR PANTHER; PTHR47966; PTHR47966; 2.
DR Pfam; PF00026; Asp; 1.
DR Pfam; PF14543; TAXi_N; 1.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 1.
DR PROSITE; PS51767; PEPTIDASE_A1; 1.
PE 1: Evidence at protein level;
KW Aspartyl protease; Coiled coil; Disulfide bond; Endoplasmic reticulum;
KW Hydrolase; Membrane; Protease; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..?
FT /evidence="ECO:0000305"
FT CHAIN ?..590
FT /note="Plasmepsin V"
FT /id="PRO_0000453926"
FT TOPO_DOM 1..544
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:25849462"
FT TRANSMEM 545..565
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 566..590
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:25849462"
FT DOMAIN 100..514
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT REGION 282..316
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 33..81
FT /evidence="ECO:0000255"
FT ACT_SITE 118
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 365
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT DISULFID 128..211
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 131..134
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 155..166
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 160..171
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 259..518
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 389..434
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT DISULFID 443..479
FT /evidence="ECO:0000250|UniProtKB:A5K302"
FT MUTAGEN 118
FT /note="D->A: Loss of catalytic activity. Loss of catalytic
FT activity; when associated with A-365 or A-365 and A-370."
FT /evidence="ECO:0000269|PubMed:20130643,
FT ECO:0000269|PubMed:20130644, ECO:0000269|PubMed:24983235"
FT MUTAGEN 133..590
FT /note="Missing: Conditional deletion at the beginning of
FT the first erythrocyte infection cycle results in no defect
FT in egress and subsequent invasion. However, in the next
FT invasion cycle, causes a severe growth defect and
FT developmental arrest between the ring and trophozoite
FT stages. Export of HRP2 into the host erythrocyte is also
FT partially impaired."
FT /evidence="ECO:0000269|PubMed:30517136"
FT MUTAGEN 365
FT /note="D->A: Loss of catalytic activity; when associated
FT with A-118 or A-118 and A-370."
FT /evidence="ECO:0000269|PubMed:20130643,
FT ECO:0000269|PubMed:24983235"
FT MUTAGEN 370
FT /note="F->A: Loss of catalytic activity; when associated
FT with A-118 and A-365."
FT /evidence="ECO:0000269|PubMed:20130643"
SQ SEQUENCE 590 AA; 68480 MW; E0108FA9E9C38832 CRC64;
MNNYFLRKEN FFILFCFVFV SIFFVSNVTI IKCNNVENKI DNVGKKIENV GKKIGDMENK
NDNVENKNDN VGNKNDNVKN ASSDLYKYKL YGDIDEYAYY FLDIDIGKPS QRISLILDTG
SSSLSFPCNG CKDCGIHMEK PYNLNYSKTS SILYCNKSNC PYGLKCVGNK CEYLQSYCEG
SQIYGFYFSD IVTLPSYNNK NKISFEKLMG CHMHEESLFL HQQATGVLGF SLTKPNGVPT
FVDLLFKHTP SLKPIYSICV SEHGGELIIG GYEPDYFLSN QKEKQKMDKS DNNSSNKGNV
SIKLKNNDKN DDEENNSKDV IVSNNVEDIV WQAITRKYYY YIKIYGLDLY GTNIMDKKEL
DMLVDSGSTF THIPENIYNQ INYYLDILCI HDMTNIYEIN KRLKLTNESL NKPLVYFEDF
KTALKNIIQN ENLCIKIVDG VQCWKSLENL PNLYITLSNN YKMIWKPSSY LYKKESFWCK
GLEKQVNNKP ILGLTFFKNK QVIFDLQQNQ IAFIESKCPS NLTSSRPRTF NEYREKENIF
LKVSYINLYC LWLLLALTIL LSLILYVRKM FYMDYFPLSD QNKSPIQEST
