TY - JOUR
T1 - Malaria parasite CelTOS targets the inner leaflet of cell membranes for pore- dependent disruption
AU - Jimah, John R.
AU - Salinas, Nichole D.
AU - Sala-Rabanal, Monica
AU - Jones, Nathaniel G.
AU - David Sibley, L.
AU - Nichols, Colin G.
AU - Schlesinger, Paul H.
AU - Tolia, Niraj H.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R56 AI080792 to NHT) and the Burroughs Wellcome Fund (to NHT). We thank J Nix and ALS Beamline 4.2.2 supported by contract DE-AC02-05CH11231. We thank W Beatty and B Anthony of the Molecular Microbiology Imaging Facil- ity, School of Medicine, Washington University in St Louis. The authors declare there are no conflicts of interest.
Publisher Copyright:
© Jimah et al.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Apicomplexan parasites contain a conserved protein CelTOS that, in malaria parasites, is essential for traversal of cells within the mammalian host and arthropod vector. However, the molecular role of CelTOS is unknown because it lacks sequence similarity to proteins of known function. Here, we determined the crystal structure of CelTOS and discovered CelTOS resembles proteins that bind to and disrupt membranes. In contrast to known membrane disruptors, CelTOS has a distinct architecture, specifically binds phosphatidic acid commonly present within the inner leaflet of plasma membranes, and potently disrupts liposomes composed of phosphatidic acid by forming pores. Microinjection of CelTOS into cells resulted in observable membrane damage. Therefore, CelTOS is unique as it achieves nearly universal inner leaflet cellular activity to enable the exit of parasites from cells during traversal. By providing novel molecular insight into cell traversal by apicomplexan parasites, our work facilitates the design of therapeutics against global pathogens.
AB - Apicomplexan parasites contain a conserved protein CelTOS that, in malaria parasites, is essential for traversal of cells within the mammalian host and arthropod vector. However, the molecular role of CelTOS is unknown because it lacks sequence similarity to proteins of known function. Here, we determined the crystal structure of CelTOS and discovered CelTOS resembles proteins that bind to and disrupt membranes. In contrast to known membrane disruptors, CelTOS has a distinct architecture, specifically binds phosphatidic acid commonly present within the inner leaflet of plasma membranes, and potently disrupts liposomes composed of phosphatidic acid by forming pores. Microinjection of CelTOS into cells resulted in observable membrane damage. Therefore, CelTOS is unique as it achieves nearly universal inner leaflet cellular activity to enable the exit of parasites from cells during traversal. By providing novel molecular insight into cell traversal by apicomplexan parasites, our work facilitates the design of therapeutics against global pathogens.
UR - http://www.scopus.com/inward/record.url?scp=85003510887&partnerID=8YFLogxK
U2 - 10.7554/eLife.20621
DO - 10.7554/eLife.20621
M3 - Article
C2 - 27906127
AN - SCOPUS:85003510887
VL - 5
JO - eLife
JF - eLife
SN - 2050-084X
IS - DECEMBER2016
M1 - e20621
ER -