Characterization and Structural Studies of the Plasmodium Falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

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Characterization and Structural Studies of the Plasmodium Falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

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Title: Characterization and Structural Studies of the Plasmodium Falciparum Ubiquitin and Nedd8 Hydrolase UCHL3
Author: Artavanis-Tsakonas, Katerina; Antos, John M.; Coleman, Bradley Ian; Comeaux, Christy Ann; Duraisingh, Manoj T.; Gaudet, Rachelle; Ploegh, Hidde L.; Weihofen, Wilhelm Andreas

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Citation: Artavanis-Tsakonas, Katerina, Wilhelm. A. Weihofen, John M. Antos, Bradley I. Coleman, Christy A. Comeaux, Manoj T. Duraisingh, Rachelle Gaudet, and Hidde L. Ploegh. 2010. Characterization and structural studies of the plasmodium falciparum ubiquitin and Nedd8 hydrolase UCHL3. Journal of Biological Chemistry 285(9): 6857-6866.
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Abstract: Like their human hosts, Plasmodium falciparum parasites rely on the ubiquitin-proteasome system for survival. We previously identified PfUCHL3, a deubiquitinating enzyme, and here we characterize its activity and changes in active site architecture upon binding to ubiquitin. We find strong evidence that PfUCHL3 is essential to parasite survival. The crystal structures of both PfUCHL3 alone and in complex with the ubiquitin-based suicide substrate UbVME suggest a rather rigid active site crossover loop that likely plays a role in restricting the size of ubiquitin adduct substrates. Molecular dynamics simulations of the structures and a model of the PfUCHL3-PfNedd8 complex allowed the identification of shared key interactions of ubiquitin and PfNedd8 with PfUCHL3, explaining the dual specificity of this enzyme. Distinct differences observed in ubiquitin binding between PfUCHL3 and its human counterpart make it likely that the parasitic DUB can be selectively targeted while leaving the human enzyme unaffected.
Published Version: doi:10.1074/jbc.M109.072405
Other Sources: http://golgi.harvard.edu/Gaudet/papers/Artavanis_JBC_2010.pdf
Terms of Use: This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAP
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4340148

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  • FAS Scholarly Articles [7501]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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