Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Edited by Thomas D. Pollard, Yale University, New Haven, CT, and approved August 21, 2017 (received for review May 5, 2017)
Significance
The malaria parasite Plasmodium falciparum actively invades host cells, using a mechanism that relies on the interaction of the motor protein myosin and actin filaments which serve as tracks. We determined the structure of stabilized P. falciparum actin 1 filaments at near-atomic resolution using single-particle electron cryomicroscopy. The high resolution of the structure allowed us to identify important positions in the filament that are essential for the temporal and spatial control of actin polymerization and play a pivotal role in host cell invasion, and thus infectivity. In general, our study provides important insights into the structural design of actin filaments.
Abstract
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: inari.kursula{at}uib.no or stefan.raunser{at}mpi-dortmund.mpg.de.
Author contributions: I.K. and S.R. designed research; S.P., E.-P.K., J.v.d.E., and J.V. performed research; S.P. analyzed data; and S.P., I.K., and S.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The electron density map after postprocessing has been deposited in the Electron Microscopy Data Bank (EMDB accession code 3805). The final model containing five actin subunits and three jasplakinolide molecules was submitted to the Protein Data Bank, www.pdb.org (PDB ID code 5OGW).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1707506114/-/DCSupplemental.
Malaria parasite F-actin structure
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Several large or long-lived animals seem strangely resistant to developing cancer. Elucidating the reasons why could lead to promising cancer-fighting strategies in humans.
Image credit: Shutterstock.com/ronnybas frimages.
PNAS Profile of NAS member and biochemist Hao Wu
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.