期刊
FEBS JOURNAL
卷 289, 期 16, 页码 4935-4962出版社
WILEY
DOI: 10.1111/febs.16378
关键词
artemisinin-resistance; hexamer; Kelch13; Plasmodium falciparum; SAXS
资金
- Science and Engineering Research Board, Department of Science and Technology, Government of India [DST ECR/2015/000387]
- Department of Biotechnology Ramalingaswami Re-entry Fellowship [BT/HRD/35/02/2006]
- University for Potential Excellence-II [245]
- Council of Scientific and Industrial Research, Government of India
This study reveals that artemisinin-resistant mutations in PfKelch13 result in stable hexameric assemblies in the BTB/POZ-KRP domains. These mutations do not affect protein assembly but alter the susceptibility to artemisinin.
The artemisinin-resistant mutations in Plasmodium falciparum (PfKelch13) identified worldwide are mostly confined to the Broad-complex, tramtrack and bric-a-brac/poxvirus and zinc-finger (BTB/POZ) and Kelch-repeat propeller (KRP) domains. To date, only two crystal structures of the BTB/POZ-KRP domains as tight dimers are available, which limits structure-based predictions and interpretation of its role(s) in inducing clinical artemisinin resistance. Our solution Small-Angle X-ray Scattering (SAXS) data analysis and shape restoration brought forth that: (a) PfKelch13 forms a stable hexamer in P6 symmetry, (b) interactions of the N-termini drive the hexameric assembly, and (c) the six KRP domains project independently in space, forming a cauldron-like architecture. We further deduce that the artemisinin-sensitive mutant A578S is packed like the wild-type protein, however, hexameric assemblies of the predominant artemisinin-resistant mutants R539T and C580Y displayed detectable differences in the spatial positioning of their BTB/POZ-KRP domains. Lastly, mapping of mutations known to enable artemisinin resistance suggested evolutionary pressure in the selection for mutations in the BTB/POZ-KRP domains. These mutations appear non-detrimental to the hexameric assembly of proteins, and yet somehow alter the flux of downstream events essential for the susceptibility to artemisinin.
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