| Autor: |
Espino-Sanchez, Tanya J., Wienkers, Henry, Marvin, Rebecca G., Nalder, Shai-anne, García-Guerrero, Aldo E., VanNatta, Peter E., Jami-Alahmadi, Yasaman, Blackwell, Amanda Mixon, Whitby, Frank G., Wohlschlegel, James A., Kleber-Emmons, Matthew T., Hill, Christopher P., Sigala, Paul A. |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 5/9/2023, Vol. 120 Issue 19, p1-12, 38p |
| Abstrakt: |
The mitochondrial electron transport chain (ETC) of Plasmodium malaria parasites is a major antimalarial drug target, but critical cytochrome (cyt) functions remain unstudied and enigmatic. Parasites express two distinct cyt c homologs (c and c-2) with unusually sparse sequence identity and uncertain fitness contributions. P.falciparum cyt c-2 is the most divergent eukaryotic cyt c homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt c homologs and the related cyt c1 for inducible knockdown. Translational repression of cyt c and cyt c1 was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt c-2 knockdown or knockout had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt c for ETC function. Biochemical and structural studies revealed that both cyt c and c-2 are hemylated by holocytochrome c synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt c-2 has an unusually open active site in which heme is stably coordinated by only a single axial amino acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent Plasmodium cytochrome c with molecular adaptations that defy a conserved role in eukaryotic evolution. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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