Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes

Shreya Endapally, Donna Frias, Magdalena Grzemska, Austin Gay, Diana R. Tomchick, Arun Radhakrishnan

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1040-1053.e17
JournalCell
Volume176
Issue number5
DOIs
StatePublished - Feb 21 2019

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Keywords

  • ALOD4
  • cholesterol
  • cholesterol homeostasis
  • lipid sensors
  • ostreolysin A
  • plasma membrane structure
  • sphingomyelin
  • sphingomyelin/cholesterol complexes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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