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Specific Lipids Supply Critical Negative Spontaneous Curvature—An Essential Component of Native Ca²⁺-Triggered Membrane Fusion

Matthew A. Churchward ^*, Tatiana Rogasevskaia ^*, David M. Brandman ^*, Houman Khosravani ^*, Phillip Nava ^¶, Jeffrey K. Atkinson ^¶ and Jens R. Coorssen ^*   

^* Department of Physiology and Biophysics, Department of Biochemistry and Molecular Biology, Department of Cell Biology and Anatomy, and Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1; and ^¶ Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1

Correspondence: Address reprint requests to Jens R. Coorssen at his present address, Chair, Molecular Physiology, School of Medicine (Bldg. 30), University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW 1797, Australia. E-mail: j.coorssen{at}uws.edu.au or jcoorsse{at}ucalgary.ca.

The Ca²⁺-triggered merger of two apposed membranes is the defining step of regulated exocytosis. CHOL is required at critical levels in secretory vesicle membranes to enable efficient, native membrane fusion: CHOL-sphingomyelin enriched microdomains organize the site and regulate fusion efficiency, and CHOL directly supports the capacity for membrane merger by virtue of its negative spontaneous curvature. Specific, structurally dissimilar lipids substitute for CHOL in supporting the ability of vesicles to fuse: diacylglycerol, T, and phosphatidylethanolamine support triggered fusion in CHOL-depleted vesicles, and this correlates quantitatively with the amount of curvature each imparts to the membrane. Lipids of lesser negative curvature than cholesterol do not support fusion. The fundamental mechanism of regulated bilayer merger requires not only a defined amount of membrane-negative curvature, but this curvature must be provided by molecules having a specific, critical spontaneous curvature. Such a local lipid composition is energetically favorable, ensuring the necessary "spontaneous" lipid rearrangements that must occur during native membrane fusion—Ca²⁺-triggered fusion pore formation and expansion. Thus, different fusion sites or vesicle types can use specific alternate lipidic components, or combinations thereof, to facilitate and modulate the fusion pore.

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