Summary for peptidase S08.012: PfSUB1 peptidase

Summary Alignment Tree Sequences Sequence features Distribution Literature Substrates Inhibitors

 

Names
MEROPS NamePfSUB1 peptidase
Other namesPfSUB-1 protease, subtilisin-like peptidase 1 (Plasmodium sp.), subtilisin-like protease 1 (Plasmodium sp.)
Name and HistoryMalaria is transmitted by a mosquito bite. The infectious stage in the malaria parasite Plasmodium falciparum life cycle is known as the sporozoite, which enters the erythrocyte and divides asexually to form merozoites. The merozoites feed on host hemoglobin, and once this has been consumed then disrupt the erythrocyte membrane and exit the cell to infect another. Disruption of the erythrocyte membrane requires release of the contents of a storage organelle called an exoneme into the lumen of the parasitophorous vacuole separating the merozoites from host cytosol (Yeoh et al., 2007). PfSUB1 is an endopeptidase that accumulates in the exoneme. Inhibition by the naturally occurring compound MRT12113 prevents egress of merozoites (Yeoh et al., 2007), which suggests PfSUB1 has a major role to play in disruption of the erythrocyte membrane.
Domain architecture
MEROPS Classification
Classification Clan SB >> Subclan (none) >> Family S8 >> Subfamily A >> S08.012
HolotypePfSUB1 peptidase (Plasmodium falciparum) (peptidase unit: 332-690), MERNUM MER0004690
History Identifier created: MEROPS 5.1 (22 June 2000)
Activity
Catalytic typeSerine
NC-IUBMBNot yet included in IUBMB recommendations.
Proteolytic eventsCutDB database (1 cleavage)
SpecificityA high-throughput study found multiple substrates for PfSUB1 (Simon de Monerri et al., 2011).
Special substrateThe synthetic substrates Ac-CIKAE+TEDDC and Ac-CIFGQ+DTAGC, both labelled by tetramethylrhodamine on the cysteines, are better substrates than Ac-LVSAD+NIDIS, which was based on the maturation cleavage site (Sajid et al., 2000, Yeoh et al., 2007).
Special inhibitorMRT12113 (Yeoh et al., 2007); the chloroisocoumarin JCP104 (Arastu-Kapur et al., 2008).
LocationStored in secretory organelles known as exonemes (Blackman et al., 1998).
PhysiologyPfSUB1 processes several merozoite surface antigens (Koussis et al., 2009) and serine repeat antigens, which are non-peptidase homologues of papain, within the parasitophorous vacuole (Yeoh et al., 2007). Processing of surface antigens prepares the merozoite for survival outside the erythrocyte.
Biological aspectsPfSUB1 is synthesized as a precursor and autoactivates, releasing an N-terminal propeptide (Sajid et al., 2000). The propeptide is a potent inhibitor of PfSUB1 (Ki ~ 5 nM) (Jean et al., 2003). A second processing event occurs in the Golgi or post-Golgi compartment, because it is sensitive to brefeldin A (Blackman et al., 1998), but the function of this event is unknown.
Contributing authorsNeil D. Rawlings, InterPro, Proteins Cluster, EMBL European Bioinformatics Institute, Hinxton, Cambridgeshire, CB10 1SD, UK
Cleavage site specificity Explanations of how to interpret the following cleavage site sequence logo and specificity matrix can be found here.
Cleavage patternVI/tks/AG/qdeScissile bonddsnt/edi/td/- (based on 23 cleavages)
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Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 0 0 10 0 0 0 0 2
Pro 0 0 0 0 0 0 1 2
Ala 0 0 13 1 2 0 2 0
Val 13 1 0 0 0 2 0 1
Leu 1 0 0 0 0 0 0 0
Ile 8 0 0 0 0 4 0 4
Met 0 0 0 0 0 0 0 0
Phe 0 2 0 0 0 0 2 0
Tyr 0 1 0 0 0 0 0 0
Trp 0 0 0 0 0 0 0 0
Ser 0 4 0 0 6 2 1 4
Thr 1 6 0 2 3 3 8 1
Cys 0 0 0 0 0 0 0 0
Asn 0 0 0 2 3 1 0 3
Gln 0 2 0 10 0 0 1 0
Asp 0 0 0 4 8 5 5 3
Glu 0 0 0 4 1 6 3 2
Lys 0 5 0 0 0 0 0 1
Arg 0 1 0 0 0 0 0 0
His 0 1 0 0 0 0 0 0