| Structural highlights
Function
FPC2A_PLAF7 Cysteine protease which cleaves native host hemoglobin and globin in the food vacuole during the asexual blood stage (PubMed:10887194, PubMed:15070727, PubMed:15964982, PubMed:16777845, PubMed:19357776, PubMed:25791019). The binding to host hemoglobin is pH-sensitive and only occurs at acidic pH (PubMed:16777845). Cleaves ankyrin and protein 4.1, two components of host erythrocyte membrane cytoskeleton required for the stability of the erythrocyte membrane, and thus may be involved in parasite release (PubMed:11463472). Preferentially cleaves substrates which have an arginine or lysine at the P1 position and a leucine or phenylalanine at the P2 position (PubMed:10887194, PubMed:19357776).[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Malaria is caused by protozoan erythrocytic parasites of the Plasmodium genus, with Plasmodium falciparum being the most dangerous and widespread disease-causing species. Falcipain-2 (FP-2) of P. falciparum is a papain-family (C1A) cysteine protease that plays an important role in the parasite life cycle by degrading erythrocyte proteins, most notably hemoglobin. Inhibition of FP-2 and its paralogues prevents parasite maturation, suggesting these proteins may be valuable targets for the design of novel antimalarial drugs, but lack of structural knowledge has impeded progress toward the rational discovery of potent, selective, and efficacious inhibitors. As a first step toward this goal, we present here the crystal structure of mature FP-2 at 3.1 A resolution, revealing novel structural features of the FP-2 subfamily proteases including a dynamic beta-hairpin hemoglobin binding motif, a flexible N-terminal alpha-helical extension, and a unique active-site cleft. We also demonstrate by biochemical methods that mature FP-2 can proteolytically process its own precursor in trans at neutral to weakly alkaline pH, that the binding of hemoglobin to FP-2 is strictly pH-dependent, and that FP-2 preferentially binds methemoglobin over hemoglobin. Because the specificity and proteolytic activity of FP-2 toward its multiple targets appears to be pH-dependent, we suggest that environmental pH may play an important role in orchestrating FP-2 function over the different life stages of the parasite. Moreover, it appears that selectivity of FP-2 for methemoglobin may represent an evolutionary adaptation to oxidative stress conditions within the host cell.
Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum.,Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL J Biol Chem. 2006 Sep 1;281(35):25425-37. Epub 2006 Jun 15. PMID:16777845[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shenai BR, Sijwali PS, Singh A, Rosenthal PJ. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J Biol Chem. 2000 Sep 15;275(37):29000-10. PMID:10887194 doi:10.1074/jbc.M004459200
- ↑ Dua M, Raphael P, Sijwali PS, Rosenthal PJ, Hanspal M. Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol Biochem Parasitol. 2001 Aug;116(1):95-9. PMID:11463472 doi:10.1016/s0166-6851(01)00306-1
- ↑ Sijwali PS, Rosenthal PJ. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4384-9. PMID:15070727 doi:10.1073/pnas.0307720101
- ↑ Pandey KC, Wang SX, Sijwali PS, Lau AL, McKerrow JH, Rosenthal PJ. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9138-43. PMID:15964982 doi:10.1073/pnas.0502368102
- ↑ Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J Biol Chem. 2006 Sep 1;281(35):25425-37. Epub 2006 Jun 15. PMID:16777845 doi:10.1074/jbc.M603776200
- ↑ Subramanian S, Hardt M, Choe Y, Niles RK, Johansen EB, Legac J, Gut J, Kerr ID, Craik CS, Rosenthal PJ. Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3. PLoS One. 2009;4(4):e5156. PMID:19357776 doi:10.1371/journal.pone.0005156
- ↑ Marques AF, Gomes PS, Oliveira PL, Rosenthal PJ, Pascutti PG, Lima LM. Allosteric regulation of the Plasmodium falciparum cysteine protease falcipain-2 by heme. Arch Biochem Biophys. 2015 May 1;573:92-9. PMID:25791019 doi:10.1016/j.abb.2015.03.007
- ↑ Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J Biol Chem. 2006 Sep 1;281(35):25425-37. Epub 2006 Jun 15. PMID:16777845 doi:10.1074/jbc.M603776200
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