PT  - JOURNAL ARTICLE
AU  - Romain Coppée
AU  - Daniel C. Jeffares
AU  - Audrey Sabbagh
AU  - Jérôme Clain
TI  - Structural evolutionary analysis predicts functional sites in the artemisinin resistance malaria protein K13
AID  - 10.1101/346668
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 346668
4099  - http://biorxiv.org/content/early/2018/06/21/346668.short
4100  - http://biorxiv.org/content/early/2018/06/21/346668.full
AB  - 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.