Goel, Nainy and Dhiman, Kanika and Kalidas, Nidhi and Mukhopadhyay, Anwesha and Ashish, Fnu and Bhattacharjee, Souvik (2022) Plasmodium falciparum Kelch13 and its artemisinin-resistant mutants assemble as hexamers in solution: a SAXS data-driven modelling study. The FEBS journal. ISSN 1742-4658
Full text not available from this repository. (Request a copy)Abstract
The artemisinin-resistant mutations in Plasmodium falciparum (PfKelch13) identified worldwide are mostly confined to the Broad-complex, tramtrack and bric-à-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.
| Item Type: | Article |
|---|---|
| Additional Information: | The copyright of this article belongs to Wiley |
| Uncontrolled Keywords: | artemisinin-resistance; hexamer Kelch13; Plasmodium falciparum SAXS |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 22 Jul 2022 04:16 |
| Last Modified: | 22 Jul 2022 04:16 |
| URI: | http://crdd.osdd.net/open/id/eprint/2976 |
Actions (login required)
 |
View Item |
