title: A conserved regulatory mode in exocytic membrane fusion revealed by Mso1p membrane interactions.
abstract: Sec1/Munc18 family proteins are important components of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated membrane fusion processes. However, the molecular interactions and the mechanisms involved in Sec1p/Munc18 control and SNARE complex assembly are not well understood. We provide evidence that Mso1p, a Sec1p- and Sec4p-binding protein, interacts with membranes to regulate membrane fusion. We identify two membrane-binding sites on Mso1p. The N-terminal region inserts into the lipid bilayer and appears to interact with the plasma membrane, whereas the C-terminal region of the protein binds phospholipids mainly through electrostatic interactions and may associate with secretory vesicles. The Mso1p membrane interactions are essential for correct subcellular localization of Mso1p-Sec1p complexes and for membrane fusion in Saccharomyces cerevisiae. These characteristics are conserved in the phosphotyrosine-binding (PTB) domain of β-amyloid precursor protein-binding Mint1, the mammalian homologue of Mso1p. Both Mint1 PTB domain and Mso1p induce vesicle aggregation/clustering in vitro, supporting a role in a membrane-associated process. The results identify Mso1p as a novel lipid-interacting protein in the SNARE complex assembly machinery. Furthermore, our data suggest that a general mode of interaction, consisting of a lipid-binding protein, a Rab family GTPase, and a Sec1/Munc18 family protein, is important in all SNARE-mediated membrane fusion events.
authors.affiliation: Cell and Molecular Biology Program, Institute of Biotechnology, FI-00014 University of Helsinki, Helsinki, Finland.
authors.forename: Marion
authors.initials: M
authors.lastname: Weber-Boyvat
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhao
authors.forename: Nina
authors.initials: N
authors.lastname: Aro
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yuan
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chernov
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.forename: Jussi
authors.initials: J
authors.lastname: Jäntti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D017124:Conserved Sequence; D005089:Exocytosis; D006801:Humans; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D051938:Munc18 Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry; D016716:PC12 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C513071:Apba1 protein, rat; C106953:MSO1 protein, S cerevisiae; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C497931:SEC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C064320:SEC4 protein, S cerevisiae; D020691:rab GTP-Binding Proteins