期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05724-1
关键词
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资金
- NIH [R01GM106717]
- Irma T. Hirschl/Monique Weill-Caulier Scholar Award
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2013R1A6A3A03064407]
- 1923 Fund
- Cofrin Center for Biological Information
- National Science Foundation [ACI-1053575]
- National Institutes of Health [R01GM116961]
- Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM106717, R01GM116961, T32GM008539] Funding Source: NIH RePORTER
Members of the TMEM16/ANO family of membrane proteins are Ca2+-activated phospholipid scramblases and/or Cl-channels. A membrane-exposed hydrophilic groove in these proteins serves as a shared translocation pathway for ions and lipids. However, the mechanism by which lipids gain access to and permeate through the groove remains poorly understood. Here, we combine quantitative scrambling assays and molecular dynamic simulations to identify the key steps regulating lipid movement through the groove. Lipid scrambling is limited by two constrictions defined by evolutionarily conserved charged and polar residues, one extracellular and the other near the membrane mid-point. The region between these constrictions is inaccessible to lipids and water molecules, suggesting that the groove is in a non-conductive conformation. A sequence of lipid-triggered reorganizations of interactions between these residues and the permeating lipids propagates from the extracellular entryway to the central constriction, allowing the groove to open and coordinate the headgroups of transiting lipids.
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