SUB2_PLAF7
ID SUB2_PLAF7 Reviewed; 1341 AA.
AC Q8IHZ5;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 25-MAY-2022, entry version 122.
DE RecName: Full=Subtilisin-like protease 2 {ECO:0000305};
DE EC=3.4.21.62 {ECO:0000269|PubMed:23834729, ECO:0000305|PubMed:16879884, ECO:0000305|PubMed:19214190};
DE AltName: Full=Merozoite surface sheddase {ECO:0000250|UniProtKB:O97364};
DE Short=MESH {ECO:0000250|UniProtKB:O97364};
DE AltName: Full=PfSUB2 {ECO:0000303|PubMed:16879884};
DE Flags: Precursor;
GN Name=SUB2 {ECO:0000303|PubMed:23834729};
GN ORFNames=PF3D7_1136900 {ECO:0000312|EMBL:CZT99035.1};
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 FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=16879884; DOI=10.1016/j.molbiopara.2006.06.010;
RA Green J.L., Hinds L., Grainger M., Knuepfer E., Holder A.A.;
RT "Plasmodium thrombospondin related apical merozoite protein (PTRAMP) is
RT shed from the surface of merozoites by PfSUB2 upon invasion of
RT erythrocytes.";
RL Mol. Biochem. Parasitol. 150:114-117(2006).
RN [3] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=19214190; DOI=10.1038/emboj.2009.22;
RA Koussis K., Withers-Martinez C., Yeoh S., Child M., Hackett F.,
RA Knuepfer E., Juliano L., Woehlbier U., Bujard H., Blackman M.J.;
RT "A multifunctional serine protease primes the malaria parasite for red
RT blood cell invasion.";
RL EMBO J. 28:725-735(2009).
RN [4] {ECO:0000305}
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, DOMAIN, PROTEOLYTIC CLEAVAGE, AND
RP MUTAGENESIS OF SER-960.
RX PubMed=23834729; DOI=10.1111/tra.12092;
RA Child M.A., Harris P.K., Collins C.R., Withers-Martinez C., Yeoh S.,
RA Blackman M.J.;
RT "Molecular determinants for subcellular trafficking of the malarial
RT sheddase PfSUB2.";
RL Traffic 14:1053-1064(2013).
RN [5]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=32109369; DOI=10.1016/j.chom.2020.02.005;
RA Favuzza P., de Lera Ruiz M., Thompson J.K., Triglia T., Ngo A.,
RA Steel R.W.J., Vavrek M., Christensen J., Healer J., Boyce C., Guo Z.,
RA Hu M., Khan T., Murgolo N., Zhao L., Penington J.S., Reaksudsan K.,
RA Jarman K., Dietrich M.H., Richardson L., Guo K.Y., Lopaticki S., Tham W.H.,
RA Rottmann M., Papenfuss T., Robbins J.A., Boddey J.A., Sleebs B.E.,
RA Sabroux H.J., McCauley J.A., Olsen D.B., Cowman A.F.;
RT "Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of
RT the Malaria Parasite Life Cycle.";
RL Cell Host Microbe 27:642-658.e12(2020).
CC -!- FUNCTION: Serine protease which plays an essential role in the shedding
CC of AMA1, MSP1 and MSP7 from the surface of the invading merozoite; this
CC step is essential for productive invasion and the release of the
CC adhesion between the erythrocyte and the merozoite (PubMed:16879884,
CC PubMed:19214190). May cleave TRAMP/PTTRAMP, thereby shedding TRAMP from
CC the merozoite surface during erythrocyte invasion (PubMed:16879884).
CC {ECO:0000269|PubMed:16879884, ECO:0000269|PubMed:19214190}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of proteins with broad specificity for peptide
CC bonds, and a preference for a large uncharged residue in P1.
CC Hydrolyzes peptide amides.; EC=3.4.21.62;
CC Evidence={ECO:0000269|PubMed:23834729, ECO:0000305|PubMed:16879884,
CC ECO:0000305|PubMed:19214190};
CC -!- ACTIVITY REGULATION: Activation may be calcium-dependent
CC (PubMed:16879884). Inhibited by the non-covalent interaction with the
CC cleaved propeptide (PubMed:16879884, PubMed:19214190).
CC {ECO:0000269|PubMed:16879884, ECO:0000269|PubMed:19214190}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23834729};
CC Single-pass type I membrane protein {ECO:0000305|PubMed:23834729}.
CC Cytoplasmic vesicle, secretory vesicle, microneme membrane
CC {ECO:0000269|PubMed:23834729}; Single-pass type I membrane protein
CC {ECO:0000305|PubMed:23834729}. Note=In mature schizonts, localizes to
CC micronemes at the merozoite apical region (PubMed:23834729).
CC Immediately after schizont rupture, secreted from the micronemes to the
CC merozoite surface where it redistributes in an actin-dependent manner
CC to accumulate at the posterior end of newly released merozoites
CC (PubMed:23834729). {ECO:0000269|PubMed:23834729}.
CC -!- DOMAIN: The propeptide domain acts as an intramolecular chaperone for
CC the folding of the catalytic domain (By similarity). Also acts as an
CC inhibitor of the catalytic domain thereby regulating SUB2 activity
CC during secretion (PubMed:16879884, PubMed:19214190).
CC {ECO:0000250|UniProtKB:O97364, ECO:0000269|PubMed:16879884,
CC ECO:0000269|PubMed:19214190}.
CC -!- DOMAIN: The transmembrane domain is required for SUB2 progression
CC through the secretory pathway. {ECO:0000269|PubMed:23834729}.
CC -!- DOMAIN: The cytoplasmic domain is required for the correct
CC redistribution at the merozoite surface and posterior capping but is
CC dispensable for its progression through the secretory pathway.
CC {ECO:0000269|PubMed:23834729}.
CC -!- PTM: Proteolytically cleaved at the N-terminus to generate a 74kDa
CC intermediate which is further processed into a 72kDa form
CC (PubMed:23834729). The first maturation cleavage is autocatalytic,
CC occurs in the ER and is necessary for the subsequent SUB2 trafficking
CC to the microneme (PubMed:23834729). The second cleavage may be mediated
CC by PMX/plasmepsin X (PubMed:32109369). {ECO:0000269|PubMed:23834729,
CC ECO:0000269|PubMed:32109369}.
CC -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01240}.
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DR EMBL; LN999945; CZT99035.1; -; Genomic_DNA.
DR RefSeq; XP_001348051.1; XM_001348015.1.
DR AlphaFoldDB; Q8IHZ5; -.
DR SMR; Q8IHZ5; -.
DR IntAct; Q8IHZ5; 2.
DR STRING; 5833.PF11_0381; -.
DR MEROPS; S08.013; -.
DR PRIDE; Q8IHZ5; -.
DR EnsemblProtists; CZT99035; CZT99035; PF3D7_1136900.
DR GeneID; 810927; -.
DR KEGG; pfa:PF3D7_1136900; -.
DR VEuPathDB; PlasmoDB:PF3D7_1136900; -.
DR HOGENOM; CLU_005094_0_0_1; -.
DR InParanoid; Q8IHZ5; -.
DR OMA; EYSTWNL; -.
DR PhylomeDB; Q8IHZ5; -.
DR Proteomes; UP000001450; Chromosome 11.
DR GO; GO:0016021; C:integral component of membrane; IDA:GeneDB.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0020026; C:merozoite dense granule; IDA:GeneDB.
DR GO; GO:0020009; C:microneme; IDA:GeneDB.
DR GO; GO:0033163; C:microneme membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008236; F:serine-type peptidase activity; IDA:GeneDB.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IMP:UniProtKB.
DR GO; GO:0051604; P:protein maturation; IDA:GeneDB.
DR GO; GO:0016485; P:protein processing; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:GeneDB.
DR Gene3D; 3.40.50.200; -; 1.
DR InterPro; IPR000209; Peptidase_S8/S53_dom.
DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf.
DR InterPro; IPR022398; Peptidase_S8_His-AS.
DR InterPro; IPR023828; Peptidase_S8_Ser-AS.
DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel.
DR InterPro; IPR040935; Pro_sub2.
DR Pfam; PF00082; Peptidase_S8; 1.
DR Pfam; PF18513; Pro_sub2; 1.
DR PRINTS; PR00723; SUBTILISIN.
DR SUPFAM; SSF52743; SSF52743; 1.
DR PROSITE; PS51892; SUBTILASE; 1.
DR PROSITE; PS00137; SUBTILASE_HIS; 1.
DR PROSITE; PS00138; SUBTILASE_SER; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Cell membrane; Cytoplasmic vesicle; Glycoprotein;
KW Hydrolase; Membrane; Protease; Reference proteome; Serine protease; Signal;
KW Transmembrane; Transmembrane helix; Zymogen.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT PROPEP 19..686
FT /note="Inhibition peptide"
FT /evidence="ECO:0000250|UniProtKB:O97364"
FT /id="PRO_0000450752"
FT CHAIN 687..1341
FT /note="Subtilisin-like protease 2"
FT /evidence="ECO:0000250|UniProtKB:O97364"
FT /id="PRO_5019506422"
FT TOPO_DOM 687..1136
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1137..1157
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1158..1341
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 726..1019
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT REGION 85..107
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 143..171
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 415..474
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 499..530
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 151..171
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 426..474
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 499..518
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 754
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 797
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 960
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT CARBOHYD 165
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 343
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 449
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 453
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 492
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 550
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 641
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 728
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 820
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 856
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 892
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 950
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1009
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1105
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT MUTAGEN 960
FT /note="S->A: Loss of the first autocatalytic maturation
FT cleavage. Impaired microneme localization and accumulation
FT in a ER-like secretory compartment."
FT /evidence="ECO:0000269|PubMed:23834729"
SQ SEQUENCE 1341 AA; 154800 MW; 990B2757CBBA03E0 CRC64;
MLNIIYVVSL ILIKFIFYKE CNNNNNYYLS NIELYNYKLR KRNRILNNNI NDRKSFLSDL
EQNYKPLFDI YELSANFEKR RKELEKKTKG EENEIEKKKE NDLEKKKENE IEKKKENDLE
KEYNDVINLL ELSLSSEYKE LNADVSNNDN SGHEENNKHK LNKKNSSNYK NDKSLDELIK
GAILKLKQNP NIKNKNMLDY DKIFKIIKEK LINKNLASNK IKGGDNEKLK EEKKQSDIST
NVEVKKDIIN DQLNKGIPTK KENKDDMINK ESNKEDITNE GKSNSLNNLN TLNNDGNIIT
KVYDHYTIVT NSNDILNDIS IDASDISKNS IGGINIPFNE NDNSSFTHQR YIVLSNNGEK
KYKIVLMTKN PKFMDMDGIY DEEEKKESLI ELNQKVNKEE NTNLYDGTGT LYYGKKSKKE
KENTQQKGGN NPNVDINILN NNNNNNNNNN SNNNSNSMND EEINYNNNNN NKESPSMFRR
FINFLSFSGN ENETEDTLIY HNKNDNSYKN KKEGTGKNND NNDPNNNNNK KILLNVDKLV
DQYLLNLKNN HTSKQELILV LKGELDLHSK NMKNVINNAK KNLEKYFKEH FKEFDKISYD
ISTPINFLCI FIPTLFDMNN MDLLKQALLI LHNDLHEYVE NWSFSSTYHT YEADYIKEQD
SVYDRSPKKK YIKASKKLYN NKYSFLNKFL NIEPLILFAK KLNSKRSNIE KEILNFLPKE
LRDYSTWNLS IIRVFNAWFL AGYGNKNVKV CVVDSGADIN HVDLNGNLYI PEYNEKYEMT
QDFYNFMVKN PTDASGHGTH VTGIIGGVAN DLGVVGVAPN ITLISLRFID GKKYGGSFHA
IKALNVCILN KAPIINASWG SSHFDVNLHL AVERLKYTLN GKGSVLIAAS GNKSNDNDIS
PLYPATFTFP HVYSVASISR NFEISPFSNY GHKSVHILAP GHHIYSTIPN NSYKIFTGTS
MAAPHVCGVS ALVYSVCYNQ GFIPQAEEVL DILTRTSIKI ISTKKRTIND SLVNAEGAVL
TTLLGGLWMQ MDCYFVKFNL EKGKKKHIPV VFSAYKKGVY ETDIVIAIIP IDGKSKIYGE
IHIPIKIVTD VNIPNFQESP RRGKNYTIDS NEAQHDEVLS YICENALYNL YEYDSHYLLA
SVILFFLALL SIFVGMIYMK SRKHSDKKCS KNLIKSNYIP EMDDGMEETQ QLQQERRQYF
RELFGENLEK NYDQHFVQDF GQDFRQDFKL GSTPDLKQYS DIDLQNKIQQ PERKTVKIII
NNFEDRKKET KRRLLKGLNY DGENAKKHDF TNESISNSRK NFKFSNNTEM KKNTIKSEDV
KIASDDNVNK AMNQLDDMFM K
