8ZLD

Crystal structure of PfHO from Plasmodium falciparum at 2.78 A

Summary for 8ZLD

• Entry DOI: 10.2210/pdb8zld/pdb
• Descriptor: Heme oxygenase, SULFATE ION (3 entities in total)
• Functional Keywords: plasmodium falciparum, apicoplast organelle, rna transcription, apicoplast genome, divergent heme oxygenase, dna binding protein
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 2
• Total formula weight: 56210.13

Authors

Caaveiro, J.M.M.,Senoo, A. (deposition date: 2024-05-18, release date: 2024-09-04, Last modification date: 2024-11-13)

Primary citation

Blackwell, A.M.,Jami-Alahmadi, Y.,Nasamu, A.S.,Kudo, S.,Senoo, A.,Slam, C.,Tsumoto, K.,Wohlschlegel, J.A.,Caaveiro, J.M.M.,Goldberg, D.E.,Sigala, P.A.
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis.
Biorxiv, 2024

PubMed Abstract: Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, 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 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.

PubMed: 38853871
DOI: 10.1101/2024.05.30.596652

Experimental method

X-RAY DIFFRACTION (2.78 Å)