Comparative structural and evolutionary analyses predict functional sites in the artemisinin resistance malaria protein K13

Numerous mutations in the Plasmodium falciparum Kelch13 (K13) protein confer resistance to artemisinin derivatives, the current front-line antimalarial drugs. K13 is an essential protein that contains BTB and Kelch-repeat propeller (KREP) domains usually found in E3 ubiquitin ligase complexes that target substrate protein(s) for ubiquitin-dependent degradation. K13 is thought to bind substrate proteins, but its functional/interaction sites and the structural alterations associated with artemisinin resistance mutations remain unknown. Here, we screened for the most evolutionarily conserved sites in the protein structure of K13 as indicators of structural and/or functional constraints. We inferred structure-dependent substitution rates at each amino acid site of the highly conserved K13 protein during the evolution of Apicomplexa parasites. We found two solvent-exposed patches of extraordinarily conserved sites likely involved in protein-protein interactions, one in BTB and the other one in KREP. The conserved patch in K13 KREP overlaps with a shallow pocket that displays a differential electrostatic surface potential, relative to neighboring sites, and that is rich in serine and arginine residues. Comparative structural and evolutionary analyses revealed that these properties were also found in the functionally-validated shallow pocket of other KREPs including that of the cancer-related KEAP1 protein. Finally, molecular dynamics simulations carried out on PfK13 R539T and C580Y artemisinin resistance mutant structures revealed some local structural destabilization of KREP but not in its shallow pocket. These findings open new avenues of research on one of the most enigmatic malaria proteins with the utmost clinical importance

Etudes fonctionnelles de mutations du gène CFTR impliquées dans la mucoviscidose

PARIS-BIUP (751062107) / SudocSudocFranceF

Multidrug-resistant Plasmodium falciparum malaria in the Greater Mekong subregion

International audienceComment on: Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. [Lancet Infect Dis. 2018

The modelling of the cathode sheath of an electrical arc in vacuum

This paper presents a simple model of the fragment in the cathode electrical arc root taking into account the physical phenomena occuring on the cathode surface and the sheath. The goal is the obtainment of characteristics values of the heat flux, the electrons, and atoms density in the sheath. Computation is carried out on a one-dimensional model with a coupling between the equation obtained in the sheath and an enthalpy model of the cathode to describe the temperature evolution. In the modelling, we introduce a friction zone above the sheath edge to characterize the heavy particle interactions. Numerical simulation shows that the ionic friction phenomenon deriving from ion–atom collision regulates the heat flux lightening the surface, and the crucial necessity to obtain a good evaluation of the cross section of the charge exchange

Numerical modelling of thermal ablation phenomena due to a cathodic spot

A numerical simulation of the ablation problem for the cathode spot that is based on the enthalpy formulation is presented and solved with a finite-element method using the Euler explicit scheme. Vaporization latent heat and ablation phenomena constitute the main difficulties of the cathodic surface erosion. We deduce characteristic information related to the cathode spot such as the energy repartition in three phases and the ablation length for different energy fluxes

Theoretical elements about cathode arc root

In this presentation authors show how it is possible to solve numerically the equation describing the heat flux in the metallic electrode situated under the cathode spot. The 1D model gives a good scale of sizes in time and length. The other phenomena that occur on the electrode surface are also presented and discusse

Artemisinin Bioactivity and Resistance in Malaria Parasites

International audienceArtemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure

Artemisinin Bioactivity and Resistance in Malaria Parasites

International audienceArtemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure

Emergence of Resistance to Atovaquone-Proguanil in Malaria Parasites: Insights From Computational Modeling and Clinical Case Reports

International audienc