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Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis.
Blackwell, Amanda Mixon; Jami-Alahmadi, Yasaman; Nasamu, Armiyaw S; Kudo, Shota; Senoo, Akinobu; Slam, Celine; Tsumoto, Kouhei; Wohlschlegel, James A; Caaveiro, Jose M M; Goldberg, Daniel E; Sigala, Paul A.
Afiliación
  • Blackwell AM; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT.
  • Jami-Alahmadi Y; Department of Biological Chemistry, University of California, Los Angeles, CA.
  • Nasamu AS; Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO.
  • Kudo S; Department of Chemistry & Biotechnology, The University of Tokyo, Tokyo, Japan.
  • Senoo A; Department of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • Slam C; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT.
  • Tsumoto K; Department of Chemistry & Biotechnology, The University of Tokyo, Tokyo, Japan.
  • Wohlschlegel JA; Department of Bioengineering, University of Tokyo, Tokyo, Japan.
  • Caaveiro JMM; Department of Biological Chemistry, University of California, Los Angeles, CA.
  • Goldberg DE; Department of Chemistry & Biotechnology, The University of Tokyo, Tokyo, Japan.
  • Sigala PA; Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO.
bioRxiv ; 2024 May 30.
Article en En | MEDLINE | ID: mdl-38853871
ABSTRACT
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum parasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest that Plasmodium repurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos