期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep38446
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资金
- CRUK [C26409/A16099]
- BBSRC [BB/J014575/1]
- EPSRC Centre for Doctoral Training Studentship from the Institute of Chemical Biology [EP/F500076/1]
- EPSRC [EP/J017566/1]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- MRC Centre for Transplantation, King's College London
- BBSRC [BB/J014575/1] Funding Source: UKRI
- EPSRC [EP/J017566/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1234377, 1377400] Funding Source: researchfish
- Cancer Research UK [16099] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/J017566/1] Funding Source: researchfish
The plasma membrane provides an essential barrier, shielding a cell from the pressures of its external environment. Pore-forming proteins, deployed by both hosts and pathogens alike, breach this barrier to lyse target cells. Intermedilysin is a cholesterol-dependent cytolysin that requires the human immune receptor CD59, in addition to cholesterol, to form giant beta-barrel pores in host membranes. Here we integrate biochemical assays with electron microscopy and atomic force microscopy to distinguish the roles of these two receptors in mediating structural transitions of pore formation. CD59 is required for the specific coordination of intermedilysin (ILY) monomers and for triggering collapse of an oligomeric prepore. Movement of Domain 2 with respect to Domain 3 of ILY is essential for forming a late prepore intermediate that releases CD59, while the role of cholesterol may be limited to insertion of the transmembrane segments. Together these data define a structural timeline for ILY pore formation and suggest a mechanism that is relevant to understanding other pore-forming toxins that also require CD59.
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