Model organisms lead the way to protein palmitoyltransferases

The acylation of proteins with palmitate and related fatty acids has been known for over 30 years, but the molecular machinery that carries out palmitoylation has only recently emerged from studies in the model organisms Saccharomyces cerevisiae and Drosophila. Two classes of protein acyltransferases (PATs) have been proposed. In yeast, members of a family of integral membrane proteins harboring a cysteine-rich domain (CRD) containing a conserved DHHC (Asp-His-His-Cys) motif are PATs for cytoplasmic signaling molecules. The DHHC-CRD protein Erf2p, together with an associated subunit Erf4p, palmitoylates yeast Ras proteins, and Akr1p catalyzes the palmitoylation of the yeast casein kinase Yck2p. The existence of a second class of PATs that modify secreted signaling proteins has been suggested from work in Drosophila. Rasp is required in vivo for the production of functional Hedgehog and shares sequence identity with membrane-bound O-acyltransferases, which suggests that it catalyzes the palmitoylation of Hedgehog. With the identification of PATs in model genetic organisms, the field is now poised to uncover their mammalian counterparts and to understand the enzymology of protein palmitoylation.

[1]  T. Putilina,et al.  The DHHC domain: A new highly conserved cysteine-rich motif , 1999, Molecular and Cellular Biochemistry.

[2]  R. Deschenes,et al.  Palmitoylation and Plasma Membrane Localization of Ras2p by a Nonclassical Trafficking Pathway in Saccharomyces cerevisiae , 2003, Molecular and Cellular Biology.

[3]  I. Weissman,et al.  Wnt proteins are lipid-modified and can act as stem cell growth factors , 2003, Nature.

[4]  R. Deschenes,et al.  New insights into the mechanisms of protein palmitoylation. , 2003, Biochemistry.

[5]  S. Harrison,et al.  Variation on an Src-like Theme , 2003, Cell.

[6]  G. Superti-Furga,et al.  A Myristoyl/Phosphotyrosine Switch Regulates c-Abl , 2003, Cell.

[7]  M. Marsh,et al.  The on-off story of protein palmitoylation. , 2003, Trends in cell biology.

[8]  G. Abecasis,et al.  Genetic variation in the 22q11 locus and susceptibility to schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Silvius.  Mechanisms of Ras Protein Targeting in Mammalian Cells , 2002, The Journal of Membrane Biology.

[10]  S. Hersch,et al.  HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. , 2002, Human molecular genetics.

[11]  R. Deschenes,et al.  Identification of a Ras Palmitoyltransferase in Saccharomyces cerevisiae * , 2002, The Journal of Biological Chemistry.

[12]  Linyi Chen,et al.  The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase , 2002, The Journal of cell biology.

[13]  D. Bredt,et al.  Protein palmitoylation: a regulator of neuronal development and function , 2002, Nature Reviews Neuroscience.

[14]  M. Mishina,et al.  Isolation and characterization of Golgi apparatus-specific GODZ with the DHHC zinc finger domain. , 2002, Biochemical and biophysical research communications.

[15]  S. Goff,et al.  Aph2, a Protein with a zf-DHHC Motif, Interacts with c-Abl and Has Pro-apoptotic Activity* , 2002, The Journal of Biological Chemistry.

[16]  Jie Fu,et al.  Differential Palmitoylation Directs the AMPA Receptor-Binding Protein ABP to Spines or to Intracellular Clusters , 2002, The Journal of Neuroscience.

[17]  T. Kadowaki,et al.  Drosophila Segment Polarity Gene Product Porcupine Stimulates the Posttranslational N-Glycosylation of Wingless in the Endoplasmic Reticulum* , 2002, The Journal of Biological Chemistry.

[18]  N. Perrimon,et al.  Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. , 2002, Development.

[19]  M. Scott,et al.  Sonic hedgehog in the nervous system: functions, modifications and mechanisms , 2002, Current Opinion in Neurobiology.

[20]  P. Beachy,et al.  Skinny Hedgehog, an Acyltransferase Required for Palmitoylation and Activity of the Hedgehog Signal , 2001, Science.

[21]  J. Treisman,et al.  Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein , 2001, Current Biology.

[22]  S. Michaelis,et al.  Topological and mutational analysis of Saccharomyces cerevisiae Ste14p, founding member of the isoprenylcysteine carboxyl methyltransferase family. , 2001, Molecular biology of the cell.

[23]  Xin Zeng,et al.  A freely diffusible form of Sonic hedgehog mediates long-range signalling , 2001, Nature.

[24]  N. G. Davis,et al.  Akr1p and the Type I Casein Kinases Act prior to the Ubiquitination Step of Yeast Endocytosis: Akr1p Is Required for Kinase Localization to the Plasma Membrane , 2000, Molecular and Cellular Biology.

[25]  K. Hofmann.  A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. , 2000, Trends in biochemical sciences.

[26]  R. Deschenes,et al.  Erf2, a Novel Gene Product That Affects the Localization and Palmitoylation of Ras2 in Saccharomyces cerevisiae , 1999, Molecular and Cellular Biology.

[27]  M. Resh.  Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. , 1999, Biochimica et biophysica acta.

[28]  R. Wides,et al.  The Drosophila STAM gene homolog is in a tight gene cluster, and its expression correlates to that of the adjacent gene ial. , 1999, Gene.

[29]  S. Eaton,et al.  Association of Sterol- and Glycosylphosphatidylinositol-linked Proteins with Drosophila Raft Lipid Microdomains* , 1999, The Journal of Biological Chemistry.

[30]  J. Whangbo,et al.  A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans. , 1999, Development.

[31]  M. Linder,et al.  Signalling functions of protein palmitoylation. , 1998, Biochimica et biophysica acta.

[32]  A. Gilman,et al.  A Cytoplasmic Acyl-Protein Thioesterase That Removes Palmitate from G Protein α Subunits and p21RAS * , 1998, The Journal of Biological Chemistry.

[33]  C. Ambrose,et al.  Identification of a Palmitic Acid-modified Form of Human Sonic hedgehog* , 1998, The Journal of Biological Chemistry.

[34]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[35]  G. Sprague,,et al.  The ankyrin repeat-containing protein Akr1p is required for the endocytosis of yeast pheromone receptors. , 1997, Molecular biology of the cell.

[36]  Andrew P. McMahon,et al.  The world according to bedgebog , 1997 .

[37]  A. McMahon,et al.  The world according to hedgehog. , 1997, Trends in genetics : TIG.

[38]  N. Perrimon,et al.  The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. , 1996, Genes & development.

[39]  Eugene V Koonin,et al.  Hedgehog Patterning Activity: Role of a Lipophilic Modification Mediated by the Carboxy-Terminal Autoprocessing Domain , 1996, Cell.

[40]  L. Hartwell,et al.  AKR1 encodes a candidate effector of the G beta gamma complex in the Saccharomyces cerevisiae pheromone response pathway and contributes to control of both cell shape and signal transduction , 1996, Molecular and cellular biology.

[41]  L. Bender,et al.  Interactions between the ankyrin repeat-containing protein Akr1p and the pheromone response pathway in Saccharomyces cerevisiae , 1996, Molecular and cellular biology.

[42]  G. Milligan,et al.  G-protein palmitoylation: regulation and functional significance. , 1995, Biochemical Society transactions.

[43]  J. Broach,et al.  Ras membrane targeting is essential for glucose signaling but not for viability in yeast. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Wigler,et al.  Mutations in the SHR5 gene of Saccharomyces cerevisiae suppress Ras function and block membrane attachment and palmitoylation of Ras proteins , 1995, Molecular and cellular biology.

[45]  A. M. Arias,et al.  Notch is required for wingless signaling in the epidermis of Drosophila , 1994, Cell.

[46]  R. Deschenes,et al.  A polybasic domain allows nonprenylated Ras proteins to function in Saccharomyces cerevisiae. , 1994, The Journal of biological chemistry.

[47]  J. Broach,et al.  Fatty acylation is important but not essential for Saccharomyces cerevisiae RAS function , 1987, Molecular and cellular biology.

[48]  A. Fujiyama,et al.  Processing and fatty acid acylation of RAS1 and RAS2 proteins in Saccharomyces cerevisiae. , 1986, Proceedings of the National Academy of Sciences of the United States of America.