NDLI: The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif

Content Provider	PubMed Central
Author	Pandey, Kailash C. Wang, Stephanie X. Sijwali, Puran S. Lau, Anthony L. Mckerrow, James H. Rosenthal, Philip J.
Copyright Year	2005
Abstract	Falcipain-2 (FP2) is a papain family cysteine protease and important hemoglobinase of erythrocytic Plasmodium falciparum parasites. Inhibitors of FP2 block hemoglobin hydrolysis and parasite development, suggesting that this enzyme is a promising target for antimalarial chemotherapy. FP2 and related plasmodial cysteine proteases have an unusual 14-aa motif near the C terminus of the catalytic domain. Recent solution of the structure of FP2 showed this motif to form a β-hairpin that is distant from the enzyme active site and protrudes out from the protein. To evaluate the function of this motif, we compared the activity of the wild-type enzyme with that of a mutant lacking 10 aa of the motif (Δ10FP2). Δ10FP2 had nearly identical activity to that of the wild-type enzyme against peptide substrates and the protein substrates casein and gelatin. However, Δ10FP2 demonstrated negligible activity against hemoglobin or globin. FP2 that was inhibited with trans-epoxysuccinyl-l-leucylamido-(4-guanidino)butane (FP2E-64) formed a complex with hemoglobin, but Δ10FP2E-64 did not, indicating that the motif mediates binding to hemoglobin independent of the active site. A peptide encoding the motif blocked hemoglobin hydrolysis, but not the hydrolysis of casein. Kinetics for the inhibition of Δ10FP2 were very similar to those for FP2 with peptidyl and protein inhibitors, but Δ10FP2 was poorly inhibited by the inhibitory prodomain of FP2. Our results indicate that FP2 utilizes an unusual motif for two specific functions, interaction with hemoglobin, its natural substrate, and interaction with the prodomain, its natural inhibitor.
Related Links	http://dx.doi.org/10.1073/pnas.0502368102
Ending Page	9143
Page Count	6
Starting Page	9138
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	26
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-06-28
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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