期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 40, 页码 10636-10641出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707506114
关键词
F-actin; Plasmodium; cryo-EM; jasplakinolide; malaria
资金
- Max Planck Society
- European Council under the European Union's Seventh Framework Programme [615984]
- Academy of Finland [257537, 265112, 292718]
- Emil Aaltonen Foundation
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Academy of Finland (AKA) [292718, 265112, 257537, 292718, 265112, 257537] Funding Source: Academy of Finland (AKA)
During their life cycle, apicomplexan parasites, such as the malaria parasite Plasmodium falciparum, use actomyosin-driven gliding motility to move and invade host cells. For this process, actin filament length and stability are temporally and spatially controlled. In contrast to canonical actin, P. falciparum actin 1 (PfAct1) does not readily polymerize into long, stable filaments. The structural basis of filament instability, which plays a pivotal role in host cell invasion, and thus infectivity, is poorly understood, largely because high-resolution structures of PfAct1 filaments were missing. Here, we report the near-atomic structure of jasplakinolide (JAS)stabilized PfAct1 filaments determined by electron cryomicroscopy. The general filament architecture is similar to that of mammalian F-actin. The high resolution of the structure allowed us to identify small but important differences at inter-and intrastrand contact sites, explaining the inherent instability of apicomplexan actin filaments. JAS binds at regular intervals inside the filament to three adjacent actin subunits, reinforcing filament stability by hydrophobic interactions. Our study reveals the high-resolution structure of a small molecule bound to F-actin, highlighting the potential of electron cryomicroscopy for structure-based drug design. Furthermore, our work serves as a strong foundation for understanding the structural design and evolution of actin filaments and their function in motility and host cell invasion of apicomplexan parasites.
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