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Structural evolutionary analysis predicts functional sites in the artemisinin resistance malaria protein K13

View ORCID ProfileRomain Coppée, Daniel C. Jeffares, Audrey Sabbagh, Jérôme Clain
doi: https://doi.org/10.1101/346668
Romain Coppée
UMR 216 MERIT, Institut de Recherche pour le Développement, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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  • ORCID record for Romain Coppée
Daniel C. Jeffares
Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK
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Audrey Sabbagh
UMR 216 MERIT, Institut de Recherche pour le Développement, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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  • For correspondence: audrey.sabbagh@parisdescartes.fr jerome.clain@parisdescartes.fr
Jérôme Clain
UMR 216 MERIT, Institut de Recherche pour le Développement, Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre National de Référence du Paludisme, Hôpital Bichat-Claude Bernard, Assistance Publique des Hôpitaux de Paris, France
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  • For correspondence: audrey.sabbagh@parisdescartes.fr jerome.clain@parisdescartes.fr
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Abstract

K13 is an essential Plasmodium falciparum protein that plays a key role in malaria resistance to artemisinins. Although K13 resembles BTB- and Kelch/propeller-containing proteins involved in ubiquitin ligase complexes, its functional sites remain uncharacterized. Using evolutionary and structural information, we searched for the most conserved K13 sites across Apicomplexa species evolution to identify sub-regions of K13 that are likely functional. An amino acid electropositive ‘patch’ in the K13 propeller domain has a dense concentration of extraordinarily conserved positions located at a shallow pocket, suggesting a role as binding surface. When applied to experimentally-characterized BTB-Kelch proteins, our strategy successfully identifies the validated substrate-binding residues within their own propeller shallow pocket. Another patch of slowly evolving sites is identified in the K13 BTB domain which partially overlaps the surface that binds to Cullin proteins in BTB-Cullin complexes. We provide candidate binding sites in K13 propeller and BTB domains for functional follow-up studies.

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Posted June 21, 2018.
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Structural evolutionary analysis predicts functional sites in the artemisinin resistance malaria protein K13
Romain Coppée, Daniel C. Jeffares, Audrey Sabbagh, Jérôme Clain
bioRxiv 346668; doi: https://doi.org/10.1101/346668
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Structural evolutionary analysis predicts functional sites in the artemisinin resistance malaria protein K13
Romain Coppée, Daniel C. Jeffares, Audrey Sabbagh, Jérôme Clain
bioRxiv 346668; doi: https://doi.org/10.1101/346668

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