scholarly journals Author response: A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance

2020 ◽  
Author(s):  
Christopher D Goodman ◽  
Taher Uddin ◽  
Natalie J Spillman ◽  
Geoffrey I McFadden
Keyword(s):  
Plasmodium Falciparum ◽  
Point Mutation ◽  
Single Point ◽  
Author Response ◽  
Single Point Mutation

scholarly journals A single point mutation in the Plasmodium falciparum ftsh1 metalloprotease confers actinonin resistance

2020 ◽  
Author(s):  
Christopher D Goodman ◽  
Taher Uddin ◽  
Natalie J Spillman ◽  
Geoffrey I McFadden
Keyword(s):  
Plasmodium Falciparum ◽  
Point Mutation ◽  
Single Point ◽  
Single Point Mutation ◽  
Post Translational Modification ◽  
Malaria Parasites ◽  
Specific Sequence ◽  
Allelic Replacement ◽  
Related Parasite

AbstractThe antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 as the target of actinonin in the related parasite Toxoplasma gondii and implicated actinonin in the inhibition of P. falciparum growth. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistant P. falciparum by in vitro selection and identified a specific sequence change in PfftsH1 associated with resistance. Re-Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance in P. falciparum. Our data unequivocally identifies PfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of “irresistible” drugs for combatting malaria.

scholarly journals A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Christopher D Goodman ◽  
Taher Uddin ◽  
Natalie J Spillman ◽  
Geoffrey I McFadden
Keyword(s):  
Plasmodium Falciparum ◽  
Point Mutation ◽  
In Vitro Selection ◽  
Single Point ◽  
Single Point Mutation ◽  
Post Translational Modification ◽  
Malaria Parasites ◽  
Specific Sequence ◽  
Allelic Replacement

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 as the target of actinonin in the related parasite Toxoplasma gondii and implicated P. falciparum FtsH1 as a likely target in malaria parasites. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistant P. falciparum by in vitro selection and identified a specific sequence change in PfFtsH1 associated with resistance. Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance in P. falciparum. Our data unequivocally identify PfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of ‘irresistible’ drugs for combatting malaria.

scholarly journals Author response: Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation

2020 ◽  
Author(s):  
Pamina Kazman ◽  
Marie-Theres Vielberg ◽  
María Daniela Pulido Cendales ◽  
Lioba Hunziger ◽  
Benedikt Weber ◽  
...  
Keyword(s):  
Point Mutation ◽  
Light Chain ◽  
Single Point ◽  
Author Response ◽  
Single Point Mutation ◽  
Amyloid Formation

scholarly journals A single point mutation converts a proton-pumping rhodopsin into a red-shifted, turn-on fluorescent sensor for chloride

2021 ◽  
Author(s):  
Jasmine N. Tutol ◽  
Jessica Lee ◽  
Hsichuan Chi ◽  
Farah N. Faizuddin ◽  
Sameera S. Abeyrathna ◽  
...  
Keyword(s):  
Point Mutation ◽  
Fluorescent Sensor ◽  
Single Point ◽  
Proton Pumping ◽  
Single Point Mutation ◽  
Turn On ◽  
Gloeobacter Violaceus

By utilizing laboratory-guided evolution, we have converted the fluorescent proton-pumping rhodopsin GR from Gloeobacter violaceus into GR1, a red-shifted, turn-on fluorescent sensor for chloride.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

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