@article{6bb47f8e23864ca9a2b4f1e3eaff85ff,
title = "Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes",
abstract = "Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present. One conformation, bound by OlyA, is induced by stoichiometric, exothermic interactions with cholesterol, properties that are consistent with sphingomyelin/cholesterol complexes. In its second conformation, sphingomyelin is free from cholesterol and does not bind OlyA. A point mutation abolishes OlyA's ability to discriminate between these two conformations. In cells, levels of sphingomyelin/cholesterol complexes are held constant over a wide range of plasma membrane cholesterol concentrations, enabling precise regulation of the chemical activity of cholesterol. The plasma membrane lipid sphingomyelin has two distinct conformations depending on the presence or absence of cholesterol.",
keywords = "ALOD4, cholesterol, cholesterol homeostasis, lipid sensors, ostreolysin A, plasma membrane structure, sphingomyelin, sphingomyelin/cholesterol complexes",
author = "Shreya Endapally and Donna Frias and Magdalena Grzemska and Austin Gay and Tomchick, {Diana R.} and Arun Radhakrishnan",
note = "Funding Information: We thank Kristina Sep{\v c}i{\'c} (University of Ljubljana, Slovenia) and Michelle Dunstone (Monash University, Australia) for kindly providing expression plasmids; Daphne Rye for assistance with hemolysis assays; Leticia Esparza, Shomanike Head, Camille Harry, Rachel Tesla, and Lisa Beatty for cell culture assistance; Helen Aronovich for assistance with crystal screening; Kristen Johnson, Anza Darehshouri, and the Electron Microscopy Core Facility at UTSW for assistance with osmium tetroxide fixation; Sarah Bayless and Britney Johnson for their assistance during early phases of this work; and Rodney Infante, Russell DeBose-Boyd, Mike Brown, Joe Goldstein, Jay Horton, and Josh Zimmerberg for valuable suggestions. This work was supported by Welch Foundation (I-1793), American Heart Association (12SDG12040267), and NIH (HL20948). Crystallographic results shown in this report were derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Funding Information: We thank Kristina Sep{\v c}i{\'c} (University of Ljubljana, Slovenia) and Michelle Dunstone (Monash University, Australia) for kindly providing expression plasmids; Daphne Rye for assistance with hemolysis assays; Leticia Esparza, Shomanike Head, Camille Harry, Rachel Tesla, and Lisa Beatty for cell culture assistance; Helen Aronovich for assistance with crystal screening; Kristen Johnson, Anza Darehshouri, and the Electron Microscopy Core Facility at UTSW for assistance with osmium tetroxide fixation; Sarah Bayless and Britney Johnson for their assistance during early phases of this work; and Rodney Infante, Russell DeBose-Boyd, Mike Brown, Joe Goldstein, Jay Horton, and Josh Zimmerberg for valuable suggestions. This work was supported by Welch Foundation ( I-1793 ), American Heart Association ( 12SDG12040267 ), and NIH ( HL20948 ). Crystallographic results shown in this report were derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = feb,
day = "21",
doi = "10.1016/j.cell.2018.12.042",
language = "English (US)",
volume = "176",
pages = "1040--1053.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}