PT  - JOURNAL ARTICLE
AU  - Romain Coppée
AU  - Daniel Jeffares
AU  - Audrey Sabbagh
AU  - Jérôme Clain
TI  - Delineating functional sites in the K13 antimalarial resistance protein through evolutionary and structural analyses
AID  - 10.1101/346668
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 346668
4099  - http://biorxiv.org/content/early/2018/06/14/346668.short
4100  - http://biorxiv.org/content/early/2018/06/14/346668.full
AB  - K13 is an essential Plasmodium falciparum protein that plays a key role in malaria resistance to artemisinins. Although K13 resembles to BTB- and Kelch/propeller-containing proteins involved in ubiquitin ligase complexes, its functional sites remain uncharacterized. Using bioinformatics analyses combining evolutionary and protein structural information, we find evidence of strong purifying selection acting on the Apicomplexa k13 gene. An electropositive amino acid “patch” in the propeller domain bears a dense concentration of extraordinarily conserved positions located at a shallow pocket, suggesting a role in mediating protein-protein interactions. 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.