title: A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport.
abstract: Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART-like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER.
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Alberto T
authors.identifier: http://orcid.org/0000-0002-2404-7351
authors.initials: AT
authors.lastname: Gatta
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Yves Y
authors.initials: YY
authors.lastname: Sere
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Calderón-Noreña
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Shamshad
authors.initials: S
authors.lastname: Cockcroft
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, United States.
authors.forename: Anant K
authors.identifier: http://orcid.org/0000-0001-6924-2698
authors.initials: AK
authors.lastname: Menon
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Tim P
authors.initials: TP
authors.lastname: Levine
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D019295:Computational Biology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C515231:Ysp2 protein, S cerevisiae
keywords: S. cerevisiae; StART protein; VASt domains; cell biology; cholesterol; ergosterol; lipid traffic; membrane contact sites; polyenes