Evolutionary divergent PEX3 is essential for glycosome biogenesis and survival of trypanosomatid parasites
| Autor: | Martin Jung, Bettina Tippler, Ann-Britt Schäfer, Renate Maier, Wolfgang Schliebs, Florent Delhommel, Stefan Gaussmann, Michael Sattler, Ralf Erdmann, Silke Oeljeklaus, Bettina Warscheid, Vishal C. Kalel, Mengqiao Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Lipoproteins
human African trypanosomiasis Protozoan Proteins Druggability BSF Computational biology Biology Microbodies Glycosome Homology (biology) Peroxins 03 medical and health sciences Tb Humans peroxisomal membrane protein Trypanosoma brucei DMSO Molecular Biology Cells Cultured 030304 developmental biology 0303 health sciences Arabidopsis Proteins 030302 biochemistry & molecular biology blood stream form Computational Biology Membrane Proteins Cell Biology Peroxisome Dimethyl sulfoxide PCF PMP procyclic form Cytosol Membrane protein Drug development HAT Trypanosomatina Biogenesis |
| DOI: | 10.22028/d291-38425 |
| Popis: | Trypanosomatid parasites cause devastating African sleeping sickness, Chagas disease, and Leishmaniasis that affect about 18 million people worldwide. Recently, we showed that the biogenesis of glycosomes could be the "Achilles' heel" of trypanosomatids suitable for the development of new therapies against trypanosomiases. This was shown for inhibitors of the import machinery of matrix proteins, while the distinct machinery for the topogenesis of glycosomal membrane proteins evaded investigation due to the lack of a druggable interface. Here we report on the identification of the highly divergent trypanosomal PEX3, a central component of the transport machinery of peroxisomal membrane proteins and the master regulator of peroxisome biogenesis. The trypanosomatid PEX3 shows very low degree of conservation and its identification was made possible by a combinatory approach identifying of PEX19-interacting proteins and secondary structure homology screening. The trypanosomal PEX3 localizes to glycosomes and directly interacts with the membrane protein import receptor PEX19. RNAi-studies revealed that the PEX3 is essential and that its depletion results in mislocalization of glycosomal proteins to the cytosol and a severe growth defect. Comparison of the parasites and human PEX3-PEX19 interface disclosed differences that might be accessible for drug development. The absolute requirement for biogenesis of glycosomes and its structural distinction from its human counterpart make PEX3 a prime drug target for the development of novel therapies against trypanosomiases. The identification paves the way for future drug development targeting PEX3, and for the analysis of additional partners involved in this crucial step of glycosome biogenesis. |
| Databáze: | OpenAIRE |
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