title: HIV-Tat Protein Forms Phosphoinositide-dependent Membrane Pores Implicated in Unconventional Protein Secretion.
abstract: HIV-Tat has been demonstrated to be secreted from cells in a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent manner. Here we show that HIV-Tat forms membrane-inserted oligomers, a process that is accompanied by changes in secondary structure with a strong increase in antiparallel β sheet content. Intriguingly, oligomerization of HIV-Tat on membrane surfaces leads to the formation of membrane pores, as demonstrated by physical membrane passage of small fluorescent tracer molecules. Although membrane binding of HIV-Tat did not strictly depend on PI(4,5)P2 but, rather, was mediated by a range of acidic membrane lipids, a functional interaction between PI(4,5)P2 and HIV-Tat was critically required for efficient membrane pore formation by HIV-Tat oligomers. These properties are strikingly similar to what has been reported previously for fibroblast growth factor 2 (FGF2), providing strong evidence of a common core mechanism of unconventional secretion shared by HIV-Tat and fibroblast growth factor 2.
authors.affiliation: From the Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany and.
authors.forename: Marcel
authors.initials: M
authors.lastname: Zeitler
authors.affiliation: From the Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany and.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Steringer
authors.affiliation: From the Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany and.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Müller
authors.affiliation: the Zentrum für Molekulare Biologie der Universität Heidelberg, Deutsches Krebsforschungszentrum-Zentrum für Molekulare Biologie der Universität Heidelberg Allianz, 69120 Heidelberg, Germany.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Mayer
authors.affiliation: From the Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany and walter.nickel@bzh.uni-heidelberg.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Nickel
mesh_terms: D002462:Cell Membrane / Q000378:metabolism* / Q000821:virology; D004591:Electrophoresis, Polyacrylamide Gel; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021381:Protein Transport; D017550:Spectroscopy, Fourier Transform Infrared; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008081:Liposomes; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2
keywords: FGF; FGF2 and membrane translocation; HIV-Tat; membrane bilayer; membrane lipid; membrane reconstitution; membrane recruitment and pore formation; phosphoinositide PI(4,5)P2; plasma membrane; unconventional protein secretion