Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Structures of Plasmodium falciparum ribosomes reveal critical dynamics during translation
Plasmodium falciparum, the mosquito-transmitted, Apicomplexan parasite, causes the most severe form of human malaria. In the asexual blood-stage, the parasite resides within erythrocytes where the parasite proliferates, multiplies and finally spreads to new erythrocytes (Jackson et al, 2011). Development of drugs targeting the ribosome, the site of protein synthesis, requires specific knowledge of its structure and work cycle, and, critically, the ways they differ from those in the human host. Here, we present five cryo-EM reconstructions of ribosomes purified from P. falciparum blood-stage schizonts at sub-nanometer resolution. Atomic models built from these density maps by flexible fitting (Trabuco et al, 2008) of a recently published structure (Wong et al, 2014) show distinct features of the P. falciparum ribosome, including its unusual dynamics, movements of 40S head region, and the notable absence of the RACK1 protein. Significantly, our study has taken advantage of new capabilities of cryo-EM, in visualizing several structures co-existing in the sample at once, at a resolution sufficient for building atomic models. We have discovered structural and dynamic features that differentiate protein synthesis in P. falciparum from that in the mammalian system. More extensive studies, using this cryo-EM methodology, of translation in the parasite will provide structural tools to develop novel anti-malarials.
This work was supported by Howard Hughes Medical Institute and National Institutes of Health [R01 GM29169 to J.F.]; National Institutes of Health [R01 AI102907, DP2 AI112219 to J.D.]; and the Swedish Research Council (to K.B.).
Trabuco LG, Villa E, Mitra K, Frank J, Schulten K (2008) Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics. Structure 16: 673-683
Wong W, Bai XC, Brown A, Fernandez IS, Hanssen E, Condron M, Tan YH, Baum J, Scheres SH (2014) Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine. eLife 3: e03080
Department of Biological Sciences