Summary for peptidase C01.063: falcipain-3

Summary Alignment Tree Sequences Sequence features Distribution Structure Literature Substrates Inhibitors

 

Names
MEROPS Namefalcipain-3
Other namesvivapain-3 (Plasmodium vivax)
Name and HistoryFalcipains are papain homologues found in the malaria parasite Plasmodium. Falcipains -2 and -3 are components of the proteolytic machinery required for the degradation of host hemoglobin to amino acids (Sijawli et al., 2001).
Domain architecture
MEROPS Classification
Classification Clan CA >> Subclan (none) >> Family C1 >> Subfamily A >> C01.063
Holotypefalcipain-3 (Plasmodium falciparum) (peptidase unit: 268-492), MERNUM MER0012048
History Identifier created: MEROPS 5.8 (19 March 2002)
Activity
Catalytic typeCysteine
NC-IUBMBNot yet included in IUBMB recommendations.
Proteolytic eventsCutDB database (77 cleavages)
SpecificityIn synthetic substrates, falcipain-3 prefers tripeptides over dipeptides (Sijawli et al., 2001). Substrate specificity studies have identified the following preferences: Leu in P2 and P1, and Ala in P3 (Cotrin et al., 2013). Site-directed mutagenesis has identified Ile94 and Pro181 as chiefly responsible for the P2 preference for Leu in P2 and the lack of hydrolysis of substrates with Arg in this position (Kolla et al., 2015).
pH optimumFalcipain-3 is active in the pH range 5.0-6.5 (Shenai et al., 2000).
Inhibitor commentsThe naturally occuring inhibitor falstatin is expressed in stages other than trophozites, the hemoglobin-feeding stage, and controls falcipain activity outside of the food vacuole (Pandey et al., 2006).
StructureFalcipain-3 is a type II transmembrane protein with a membrane-spanning domain at the N-terminus. Unusually for a papain-like cysteine endopeptidase, the maturation cleavage site is lacking and mature falcipain-3 has an N-terminal extension of ~20 residues (Shenai et al., 2000). Tertiary structures have been solved for the enzyme in complex with inhibitors (Kerr et al., 2009, Kerr et al., 2009). The structures reveal two motifs unique to the falcipains, known as FP3nose, which mediated protein folding, and FP3arm, which interacts with hemoglobin.
LocationFalcipain-3 is a type II integral membrane protein located in the food vacuole (Shenai et al., 2000).
Biological aspectsFalcipain-3 is expressed in the late trophozoite/early schizont stage (Dahl & Rosenthal, 2005). Falcipain-3 activates plasmepsins (Drew et al., 2008), and both plasmepsins and falcipains -2, -2' and -3 are required for hemoglobin digestion in the food vacuole. Falcipain-3 can release kinins from kininogen (Bagnaresi et al., 2012).
Pharmaceutical relevanceFalcipain-3 is a pharmacological target for antimalarial drugs and numerous synthetic inhibitors have been synthesized (Musyoka et al., 2015, Conroy et al., 2014, Weldon et al., 2014, Rathi et al., 2013).
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 pattern-/-/l/-Scissile bond-/-/-/- (based on 126 cleavages)
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Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 8 7 4 10 7 6 10 9
Pro 9 6 3 2 4 8 7 4
Ala 10 15 4 15 25 13 7 11
Val 6 15 20 6 4 10 7 12
Leu 8 23 37 13 18 11 14 10
Ile 0 1 0 0 0 0 0 0
Met 2 4 2 0 1 1 1 1
Phe 9 5 10 6 6 7 7 4
Tyr 1 1 7 1 1 3 5 1
Trp 2 1 1 1 2 1 3 0
Ser 7 6 6 9 12 7 8 4
Thr 6 6 9 8 5 7 2 11
Cys 1 1 0 1 2 0 1 0
Asn 5 5 1 4 5 2 2 3
Gln 1 2 3 4 1 0 3 1
Asp 7 4 6 5 4 4 8 10
Glu 4 4 7 4 1 6 13 5
Lys 4 8 3 17 7 6 6 6
Arg 3 3 1 14 3 1 3 2
His 6 4 2 5 6 9 7 6
Specificity from combinatorial peptides
 
Organism comment P4 P3 P2 P1 P1' P2' P3' P4' optimal substrate fluorophore or acceptor-donor pair Reference
Plasmodium falciparum recombinant broad L/F L R/K - - - - broad-LLR AMC Ramjee et al., 2006
Plasmodium falciparum recombinant H/N/broad n/P/K/broad L R/Q/T/broad - - - - HnLR ACC Subramanian et al., 2009
Plasmodium falciparum recombinant - - L R A - - - xxLR+Axxx Abz-Tyr(NO2) Ramjee et al., 2006