Trafficking and signaling by fatty-acylated and prenylated proteins

A wide variety of signaling proteins are modified by covalently linked fatty acids and/or prenyl groups. These hydrophobic moieties, which include myristate, palmitate, farnesyl and geranylgeranyl, are more than just fat: they provide distinct information that modulates the specificity and efficiency of signal transduction. Recent studies show that lipid modification influences the movement of a signaling protein within the cell and its final destination. Protein lipidation can also confer reversible association with membranes and other signaling proteins. These findings provide new insights into the biochemical and biophysical mechanisms that regulate membrane targeting, trafficking and signaling by lipid-modified proteins.

[1]  C. Thompson,et al.  PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. , 2006, Molecular cell.

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

[3]  Robert G. Parton,et al.  GTP-dependent segregation of H-ras from lipid rafts is required for biological activity , 2001, Nature Cell Biology.

[4]  J. B. Sajous,et al.  Ras signalling on the endoplasmic reticulum and the Golgi , 2002, Nature Cell Biology.

[5]  M. Seabra,et al.  Fatty acylation and prenylation of proteins: what's hot in fat. , 2005, Current opinion in cell biology.

[6]  M. Resh,et al.  Myristylation and palmitylation of Src family members: The fats of the matter , 1994, Cell.

[7]  M. Resh,et al.  Palmitoylation of the EGFR ligand Spitz by Rasp increases Spitz activity by restricting its diffusion. , 2006, Developmental cell.

[8]  S. Korsmeyer,et al.  Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. , 2000, Science.

[9]  H. Hofemeister,et al.  Association of prenylated proteins with the plasma membrane and the inner nuclear membrane is mediated by the same membrane-targeting motifs. , 2000, Molecular biology of the cell.

[10]  Yun Lu,et al.  Mass Spectrometric Analysis of GAP-43/Neuromodulin Reveals the Presence of a Variety of Fatty Acylated Species* , 2002, The Journal of Biological Chemistry.

[11]  Herbert Waldmann,et al.  Structure of Rab GDP-Dissociation Inhibitor in Complex with Prenylated YPT1 GTPase , 2003, Science.

[12]  M. Resh,et al.  Heterogeneous Fatty Acylation of Src Family Kinases with Polyunsaturated Fatty Acids Regulates Raft Localization and Signal Transduction* , 2001, The Journal of Biological Chemistry.

[13]  M. Resh,et al.  Rapid Plasma Membrane Anchoring of Newly Synthesized p59  fyn: Selective Requirement for NH2-Terminal Myristoylation and Palmitoylation at Cysteine-3 , 1997, The Journal of cell biology.

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

[15]  T. Morimoto,et al.  Endomembrane Trafficking of Ras The CAAX Motif Targets Proteins to the ER and Golgi , 1999, Cell.

[16]  A. Aderem,et al.  The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions. , 1995, Trends in biochemical sciences.

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

[18]  N. Ben-Tal,et al.  Electrostatics and the membrane association of Src: theory and experiment. , 1998, Biochemistry.

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

[20]  M. Resh Membrane targeting of lipid modified signal transduction proteins. , 2004, Sub-cellular biochemistry.

[21]  T. Utsumi,et al.  C‐terminal 15 kDa fragment of cytoskeletal actin is posttranslationally N‐myristoylated upon caspase‐mediated cleavage and targeted to mitochondria , 2003, FEBS letters.

[22]  A. Gilman,et al.  Persistent membrane association of activated and depalmitoylated G protein α subunits , 1999 .

[23]  T. Utsumi,et al.  Posttranslational N-Myristoylation Is Required for the Anti-apoptotic Activity of Human tGelsolin, the C-terminal Caspase Cleavage Product of Human Gelsolin* , 2006, Journal of Biological Chemistry.

[24]  A. Álvarez-Barrientos,et al.  N-terminal palmitoylation within the appropriate amino acid environment conveys on NOS2 the ability to progress along the intracellular sorting pathways , 2006, Journal of Cell Science.

[25]  J. Hancock,et al.  H-ras but Not K-ras Traffics to the Plasma Membrane through the Exocytic Pathway , 2000, Molecular and Cellular Biology.

[26]  G. Plummer,et al.  Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Fukata,et al.  Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. , 2006, Immunity.

[28]  B Honig,et al.  Electrostatic interaction of myristoylated proteins with membranes: simple physics, complicated biology. , 1997, Structure.

[29]  S. Leppla,et al.  Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis , 2006, The Journal of cell biology.

[30]  R. M. Peitzsch,et al.  Binding of acylated peptides and fatty acids to phospholipid vesicles: pertinence to myristoylated proteins. , 1993, Biochemistry.

[31]  S. Colombo,et al.  N-myristoylation determines dual targeting of mammalian NADH-cytochrome b(5) reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning , 2005, The Journal of cell biology.

[32]  Charles D Smith,et al.  Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis , 2005, Molecular Cancer Research.

[33]  R. Leventis,et al.  K-ras4B and prenylated proteins lacking "second signals" associate dynamically with cellular membranes. , 2005, Molecular biology of the cell.

[34]  T. Meyer,et al.  Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulin , 2005, The Journal of cell biology.

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

[36]  T. Nakatsu,et al.  Crystal structure of a myristoylated CAP‐23/NAP‐22 N‐terminal domain complexed with Ca2+/calmodulin , 2004, The EMBO journal.

[37]  M. Bouvier,et al.  Role of palmitoylation/depalmitoylation reactions in G-protein-coupled receptor function. , 2003, Pharmacology & therapeutics.

[38]  S. Sebti Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. , 2005, Cancer cell.

[39]  M. Marsh,et al.  Trafficking of an Acylated Cytosolic Protein: Newly Synthesized p56lck Travels to the Plasma Membrane via the Exocytic Pathway , 1999, The Journal of cell biology.

[40]  C. Marshall,et al.  A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21 ras to the plasma membrane , 1990, Cell.

[41]  Y. Percherancier,et al.  Palmitoylation-dependent Control of Degradation, Life Span, and Membrane Expression of the CCR5 Receptor* , 2001, The Journal of Biological Chemistry.

[42]  Sebastian Maurer-Stroh,et al.  N-terminal N-myristoylation of proteins: prediction of substrate proteins from amino acid sequence. , 2002, Journal of molecular biology.

[43]  Gregory R. Hoffman,et al.  Structure of the Rho Family GTP-Binding Protein Cdc42 in Complex with the Multifunctional Regulator RhoGDI , 2000, Cell.

[44]  R. Leventis,et al.  Lipid-modified, cysteinyl-containing peptides of diverse structures are efficiently S-acylated at the plasma membrane of mammalian cells , 1996, The Journal of cell biology.

[45]  C. Marshall,et al.  All ras proteins are polyisoprenylated but only some are palmitoylated , 1989, Cell.

[46]  J. Smotrys,et al.  Palmitoylation of intracellular signaling proteins: regulation and function. , 2004, Annual review of biochemistry.

[47]  G. Fishell,et al.  An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. , 2001, Developmental biology.

[48]  P. Weigel,et al.  Nonpalmitoylated Human Asialoglycoprotein Receptors Recycle Constitutively but Are Defective in Coated Pit-mediated Endocytosis, Dissociation, and Delivery of Ligand to Lysosomes* , 2002, The Journal of Biological Chemistry.

[49]  C. Ungermann,et al.  Palmitoylation determines the function of Vac8 at the yeast vacuole , 2006, Journal of Cell Science.

[50]  M. Bergo,et al.  N-Myristoyltransferase 1 Is Essential in Early Mouse Development* , 2005, Journal of Biological Chemistry.

[51]  H. Waldmann,et al.  S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts. , 1997, Biochemistry.

[52]  Maureen P. Boyle,et al.  Palmitoylation regulates plasma membrane–nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family , 2005, The Journal of cell biology.

[53]  Yun Lu,et al.  The N-terminal SH4 Region of the Src Family Kinase Fyn Is Modified by Methylation and Heterogeneous Fatty Acylation , 2004, Journal of Biological Chemistry.

[54]  Kousuke Kasahara,et al.  Trafficking of Lyn through the Golgi caveolin involves the charged residues on αE and αI helices in the kinase domain , 2004, The Journal of cell biology.

[55]  J. Lippincott-Schwartz,et al.  Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway , 2005, The Journal of cell biology.

[56]  M. Bouvier,et al.  Distinct Subcellular Localization for Constitutive and Agonist-modulated Palmitoylation of the Human δ Opioid Receptor* , 2006, Journal of Biological Chemistry.

[57]  Yu Xue,et al.  CSS-Palm: palmitoylation site prediction with a clustering and scoring strategy (CSS) , 2006, Bioinform..

[58]  J. Gordon,et al.  The Biology and Enzymology of ProteinN-Myristoylation* 210 , 2001, The Journal of Biological Chemistry.

[59]  Deepti Chaturvedi,et al.  Drosophila Wnt-1 Undergoes a Hydrophobic Modification and Is Targeted to Lipid Rafts, a Process That Requires Porcupine* , 2004, Journal of Biological Chemistry.

[60]  H. Bourne,et al.  Activation-induced subcellular redistribution of Gs alpha. , 1996, Molecular biology of the cell.

[61]  L. Xue,et al.  A Palmitoylation Switch Mechanism in the Regulation of the Visual Cycle , 2004, Cell.

[62]  Robert G. Parton,et al.  Direct visualization of Ras proteins in spatially distinct cell surface microdomains , 2003, The Journal of cell biology.

[63]  M. Y. Degtyarev,et al.  The stoichiometry of G alpha(s) palmitoylation in its basal and activated states. , 1997, Biochemistry.

[64]  O. Weisz,et al.  Recycling of MUC1 Is Dependent on Its Palmitoylation* , 2006, Journal of Biological Chemistry.

[65]  J. Yates,et al.  Global Analysis of Protein Palmitoylation in Yeast , 2006, Cell.

[66]  H. Waldmann,et al.  Membrane insertion of a lipidated ras peptide studied by FTIR, solid-state NMR, and neutron diffraction spectroscopy. , 2003, Journal of the American Chemical Society.

[67]  M. Resh,et al.  Inhibition of Protein Palmitoylation, Raft Localization, and T Cell Signaling by 2-Bromopalmitate and Polyunsaturated Fatty Acids* , 2000, The Journal of Biological Chemistry.

[68]  Karen K. Y. Lam,et al.  Palmitoylation by the DHHC protein Pfa4 regulates the ER exit of Chs3 , 2006, The Journal of cell biology.

[69]  Kai Simons,et al.  Lipid rafts and signal transduction , 2000, Nature Reviews Molecular Cell Biology.

[70]  Herbert Waldmann,et al.  An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms , 2005, Science.

[71]  C. Futter,et al.  Farnesyltransferase inhibitors disrupt EGF receptor traffic through modulation of the RhoB GTPase , 2004, Journal of Cell Science.

[72]  J. Goldberg,et al.  Structural Basis for Activation of ARF GTPase Mechanisms of Guanine Nucleotide Exchange and GTP–Myristoyl Switching , 1998, Cell.

[73]  R. Deschenes,et al.  Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases Published, JLR Papers in Press, April 1, 2006. , 2006, Journal of Lipid Research.

[74]  L. Ruel,et al.  Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia , 2006, Development.

[75]  Neal Sweeney,et al.  Synaptic Strength Regulated by Palmitate Cycling on PSD-95 , 2002, Cell.

[76]  R. Doms,et al.  Palmitoylation of CCR5 Is Critical for Receptor Trafficking and Efficient Activation of Intracellular Signaling Pathways* , 2001, The Journal of Biological Chemistry.

[77]  F. L'Heureux,et al.  Fluorimetric evaluation of the affinities of isoprenylated peptides for lipid bilayers. , 1994, Biochemistry.

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

[79]  D. Manning,et al.  Regulation of G proteins by covalent modification , 2001, Oncogene.

[80]  Suzanne Eaton,et al.  Lipoprotein particles are required for Hedgehog and Wingless signalling , 2005, Nature.

[81]  D. Murray,et al.  Plasma membrane phosphoinositide organization by protein electrostatics , 2005, Nature.

[82]  J. Hancock,et al.  Three Separable Domains Regulate GTP-Dependent Association of H-ras with the Plasma Membrane , 2004, Molecular and Cellular Biology.

[83]  Lu Gan,et al.  Palmitoylation of huntingtin by HIP14is essential for its trafficking and function , 2006, Nature Neuroscience.

[84]  R. Gibbs,et al.  Geranylgeranyl switching regulates GDI-Rab GTPase recycling. , 2003, Structure.

[85]  A. Gomes,et al.  Membrane targeting of Rab GTPases is influenced by the prenylation motif. , 2003, Molecular biology of the cell.

[86]  Barry Honig,et al.  Retroviral matrix domains share electrostatic homology: models for membrane binding function throughout the viral life cycle. , 2005, Structure.

[87]  E. Krause,et al.  Gαs is palmitoylated at the N‐terminal glycine , 2003 .

[88]  J. Treisman,et al.  Lipid Modification of Secreted Signaling Proteins , 2006, Cell cycle.

[89]  T. Asano,et al.  Palmitoylation of the canine histamine H2 receptor occurs at Cys(305) and is important for cell surface targeting. , 2001, Biochimica et biophysica acta.

[90]  M. Resh,et al.  Membrane binding of myristylated peptides corresponding to the NH2 terminus of Src. , 1994, Biochemistry.

[91]  M. Resh,et al.  Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Philip A Beachy,et al.  Novel lipid modifications of secreted protein signals. , 2004, Annual review of biochemistry.

[93]  G. Milligan,et al.  Palmitoylation Regulates Regulator of G-protein Signaling (RGS) 16 Function , 2003, Journal of Biological Chemistry.

[94]  Peter J. Cullen,et al.  Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1 , 2003, Nature.

[95]  M Ikura,et al.  Portrait of a myristoyl switch protein. , 1996, Current opinion in structural biology.