Pospich, S., Kumpula, E., von der Ecken, J., Vahokoski, J., Kursula, I., Raunser, S. (2017) Near-atomic structure of jasplakinolide-stabilized malaria parasite F-actin reveals the structural basis of filament instability. Proceedings of the National Academy of Sciences, 114 (40), 10636-10641. doi:10.1073/pnas.1707506114
Near-atomic structure of jasplakinolide-stabilized malaria parasite F-actin reveals the structural basis of filament instability
|Author:||Pospich, Sabrina1; Kumpula, Esa-Pekka2,3; von der Ecken, Julian1;|
1Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology
2Biocenter Oulu, University of Oulu
3Faculty of Biochemistry and Molecular Medicine, University of Oulu
4Department of Biomedicine, University of Bergen
|Online Access:||PDF Full Text (PDF, 1.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201803206087
National Academy of Sciences of the United States of America,
|Publish Date:|| 2018-03-20
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.
Proceedings of the National Academy of Sciences of the United States of America
|Pages:||10636 - 10641|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by the Max Planck Society (S.R.); the European Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) (Grant 615984 to S.R.); the Academy of Finland (Grants 257537, 265112, and 292718 to I.K.); and the Emil Aaltonen, Sigrid Jusélius, and Jane and Aatos Erkko Foundations (I.K.).
|Academy of Finland Grant Number:||
257537 (Academy of Finland Funding decision)
265112 (Academy of Finland Funding decision)
292718 (Academy of Finland Funding decision)
Copyright © 2018 National Academy of Sciences. Published in this repository with the kind permission of the publisher.