Structural characterization and inhibition of the Plasmodium Atg8–Atg3 interaction

The autophagy-related proteins are thought to serve multiple functions in Plasmodium and are considered essential to parasite survival and development. We have studied two key interacting proteins, Atg8 and Atg3, of the autophagy pathway in Plasmodium falciparum. These proteins are vital for the for...

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Bibliographic Details
Published in:	Journal of structural biology Vol. 180; no. 3; pp. 551 - 562
Main Authors:	Hain, Adelaide U.P., Weltzer, Ryan R., Hammond, Holly, Jayabalasingham, Bamini, Dinglasan, Rhoel R., Graham, David R.M., Colquhoun, David R., Coppens, Isabelle, Bosch, Jürgen
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-12-2012
Subjects:	Amino Acid Sequence Antimalarials - chemistry Antimalarials - pharmacology Autophagy Autophagy - drug effects Binding Sites Crystallography, X-Ray Drug Discovery Escherichia coli - genetics Fragment library Fragment-based drug discovery Malaria Molecular Docking Simulation Molecular Sequence Data Oligopeptides - chemistry Oligopeptides - metabolism Plasmodium Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Plasmodium falciparum - metabolism Protein Binding Protein Structure, Tertiary Protein–protein interaction Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - chemistry Protozoan Proteins - genetics Pyrogallol - chemistry Pyrogallol - pharmacology Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Recombinant Proteins - genetics Sequence Homology, Amino Acid Species Specificity Surface plasmon resonance Ubiquitin-Conjugating Enzymes - antagonists & inhibitors Ubiquitin-Conjugating Enzymes - chemistry Ubiquitin-Conjugating Enzymes - genetics X-ray crystallography RU IFA Autophagy Protein–protein interaction X-ray crystallography Plasmodium SD Pb RBC SPR Fragment-based drug discovery Pf EMSA Tm WT Fragment library TSA Malaria AIM Pv CM p.i Ub Atg r.m.s.d Surface plasmon resonance
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Summary:	The autophagy-related proteins are thought to serve multiple functions in Plasmodium and are considered essential to parasite survival and development. We have studied two key interacting proteins, Atg8 and Atg3, of the autophagy pathway in Plasmodium falciparum. These proteins are vital for the formation and elongation of the autophagosome and essential to the process of macroautophagy. Autophagy may be required for conversion of the sporozoite into erythrocytic-infective merozoites and may be crucial for other functions during asexual blood stages. Here we describe the identification of an Atg8 family interacting motif (AIM) in Plasmodium Atg3, which binds Plasmodium Atg8. We determined the co-crystal structure of PfAtg8 with a short Atg3103–110 peptide, corresponding to this motif, to 2.2Å resolution. Our in vitro interaction studies are in agreement with our X-ray crystal structure. Furthermore they suggest an important role for a unique Apicomplexan loop absent from human Atg8 homologues. Prevention of the protein–protein interaction of full length PfAtg8 with PfAtg3 was achieved at low micromolar concentrations with a small molecule, 1,2,3-trihydroxybenzene. Together our structural and interaction studies represent a starting point for future antimalarial drug discovery and design for this novel protein–protein interaction.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1047-8477 1095-8657
DOI:	10.1016/j.jsb.2012.09.001