Abstract
Covalent attachment of lipophilic moieties to proteins influences interaction with membranes and membrane microdomains, as well as signal transduction. The most common forms of fatty acylation include modification of the N-terminal glycine of proteins by N-myristoylation and/or attachment of palmitate to internal cysteine residues. Protein prenylation involves attachment of farnesyl or geranylgeranyl moieties via thio-ether linkage to cysteine residues at or near the C-terminus. Attachment of each of these lipophilic groups is catalyzed by a distinct enzyme or set of enzymes: N-myristoyl transferase for N-myristoylation, palmitoyl acyl transferases for palmitoylation, and farnesyl or geranylgeranyl transferases for prenylation. The distinct nature of the lipid modification determines the strength of membrane interaction of the modified protein as well as the specificity of membrane targeting. Clusters of basic residues can also synergize with the lipophilic group to promote membrane binding and targeting. The final destination of the modified protein is influenced by multiple factors, including the localization of the modifying enzymes, protein/protein interactions, and the lipid composition of the acceptor membrane. In particular, much interest has been focused on the ability of fatty acylated proteins to preferentially partition into membrane rafts, subdomains of the plasma membrane that are enriched in cholesterol and glycosphingolipids. Lipid raft localization is necessary for efficient signal transduction in a wide variety of systems, including signaling by T and B cell receptors, Ras, and growth factor receptors. However, certain membrane subdomains, such as caveolae, can serve as reservoirs for inactive signaling proteins. Heterogeneity in the types of membrane subdomains, as well as in the types of lipophilic groups that are attached to proteins, provide an additional level of complexity in the regulation of signaling by membrane bound proteins.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Alland, L., Peseckis, S.M., Atherton, R.E., Berthiaume, L., and Resh, M.D. (1994). Dual Myristylation and Palmitylation of Src Family Member p59fyn Affects Subcellular Localization. J. Biol. Chem. 269, 16701–16705.
Anderson, R.G. and Jacobson, K. (2002). A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science 296, 1821–1825.
Anderson, R.G.W. (1998). The Caveolae Membrane System. Annu. Rev. Biochem. 67, 199–225.
Apolloni, A., Prior, I.A., Lindsay, M., Parton, R.G., and Hancock, J.F. (2000). H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol. 20, 2475–87.
Arcaro, A., Grégoire, C., Boucheron, N., Palmer, E., Malissen, B., and Luescher, I.F. (2000). Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function. J. Immunol. 165, 2068–2076.
Bano, M.D., Jackson, D.S., and Magee, A.I. (1998). Pseudo-enzymatic S-acylation of a myristoylated Yes protein tyrosine kinase peptide in vitro may reflect non-enzymatic S-acylation in vivo. Biochem. J. 330, 723–731.
Berthiaume, L., Peseckis, S.M., and Resh, M.D. (1995). Synthesis and use of lodo-fatty acid analogs. Meth. Enzymol. 250, 454–466.
Brown, D.A. and London, E. (1998). Functions of Lipid Rafts in Biological Membranes. Annu rev. Cell Dev. Biol. 14, 111–136.
Brown, D.A. and London, E. (2000). Structure and function of Sphingolipid and Cholesterol rich Membrane Rafts. J. Biol. Chem. 275, 17221–17224.
Casey, P.J., Thissen, J.A., and Moomaw, J.F. (1991). Enzymatic modification of proteins with a geranylgeranyl isoprenoid. Proc. Natl. Acad. Sci. USA 88, 8631–8635.
Chen, X. and Resh, M.D. (2002). Cholesterol Depletion from the Plasma Membrane Triggers Ligand-independent Activation of the Epidermal Growth Factor Receptor. J. Biol. Chem. 277, 49631–49637.
Cheng, P.C., Dykstra, M.L., Mitchell, R.N., and Pierce, S.K. (1999). A role for lipid rafts in B cell antigen receptor signaling and antigen targeting. J. Exp. Med. 190, 1549–1560.
Choy, E., Chiu, V.K., Silletti, J., Feoktistov, M., Morimoto, T., Michaelson, D., Ivanov, I.E., and Philips, M.R. (1999). Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69–80.
Degtyarev, M.Y., Spiegel, A.M., and Jones, T.L.Z. (1994). Palmitoylation of a G Protein Subunit Requires Membrane Localization Not Myristoylation. J. Biol. Chem. 269, 30898–30903.
Duncan, J.A. and Gilman, A.G. (1996). Autoacylation of G Protein a Subunits. J. Biol. Chem. 271, 23594–23600.
Duncan, J.A. and Gilman, A.G. (1998). A Cytoplasmic Acyl-Protein Thioesterase that Removes Palmitate from G Protein a Subunits and p21Ras. J. Biol. Chem. 273, 15830–15837.
Dunphy, J.T., Greentree, W.K., Manahan, C.L., and Linder, M.E. (1996). G-protein palmitoyltransferase activity is enriched in plasma membranes. J. Biol. Chem. 271, 7154–7159.
Dunphy, J.T., Schroeder, H., Leventis, R., Greentree, W.K., Knudsen, J.K., Silvius, J.R., and Linder, M.E. (2000). Differential effects of acyl-CoA binding protein on enzymatic and non-enzymatic thioacylation of protein and peptide substrates. Biochim. Biophys. Acta 1485, 185–198.
El-Husseini, A.-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R.A., and Bredt, D.S. (2002). Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108, 849–863.
Evanko, D.S., Thiyagarajan, M.M., Siderovski, D.P., and Wedegaertner, P.B. (2001). Gßy isoforms selectively rescue plasma membrane localization and palmitoylation of mutant Gas and Gaq. J. Biol. Chem. 276, 23945–23953.
Feron, O., Michel, J.B., Sase, K., and Michel, T. (1998). Dynamic regulation of endothelial nitric oxide synthase: complementary roles of dual acylation and caveolin interactions. Biochemistry 37, 193–200.
Fishburn, C.S., Pollitt, S.K., and Bourne, H.R. (2000). Localization of a peripheral membrane
protein: Gbetagannna targets Galpha(Z). Proc Natl Acad. Sci. USA 97, 1085–1090. Fukada, Y. (1995). Prenylation and Carboxylmethylation of G-Protein y Subunit. Meth. Enzymol. 250, 91–105.
Galbiati, E, Volonte, D., Meani, D., Milligan, G., Lublin, D.M., Lisanti, M.P., and Parenti, M. (1999). The Dually Acylated NH2-terminal Domain of Gilalpha Is Sufficient to Target a Green Fluorescent Protein Reporter to Caveolin-enriched Plasma Membrane Domains. Palmitoylation of caveolin-1 is required for the recognition of dually acylated G-protein a subunits in vivo. J. Biol. Chem. 274, 5843–5850.
Hancock, J.R., Cadwallader, K., Paterson, H., and Marshall, C.J. (1991). A CAAX or a CAAL motif and a Second Signal are Sufficient for Plasma Membrane Targeting of Ras Proteins. EMBO J. 10, 4033–4039.
Higuchi, M., Izumi, K.M., and Kieff, E. (2001). Epstein-Barr virus latent-infection membrane proteins are palmitoylated and raft-associated: protein 1 binds to the cytoskeleton through TNF receptor cytoplasmic factors. Proc. Natl Acad. Sci. USA 98, 4675–4680.
Janes, P.W., Ley, S.C., and Magee, A.I. (1999). Aggregation of Lipid Rafts Accompanies Signaling Via the T Cell Antigen Receptor. J. Cell Biol. 147, 447–461.
Kabouridis, P.S., Magee, A.I., and Ley, S.C. (1997). S-acylation of Lek protein tyrosine kinase is essential for its signalling function in T lymphocytes. EMBO J. 16, 4983–4998.
Leventis, R., Juel, G., Knudsen, J.K., and Silvius, J.R. (1997). Acyl-CoA binding proteins inhibit the nonenzymic S-acylation of cysteinyl-containing peptide sequences by long-chain acyl-CoAs. Biochemistry 36, 5546–5553.
Liang, X., Lu, Y., Neubert, T.A., and Resh, M.D. (2002). Mass spectrometric analysis of GAP-43/neuromodulin reveals the presence of a variety of fatty acylated species. J. Biol. Chem. 277, 33032–33040.
Liang, X., Nazarian, A., Erdjument-Bromage, H., Bornmann, W, Tempst, P, and Resh, M.D. (2001). Heterogeneous fatty acylation of Src family kinases with polyunsaturated fatty acids regulates raft localization and signal transduction. J. Biol. Chem. 276, 30987–30994.
Lindwasser, O.W. and Resh, M.D. (2001). Multimerization of human immunodeficiency virus type 1 Gag promotes its localization to barges, raft-like membrane microdomains. J. Virol. 75, 7913–7924.
Lindwasser, O.W. and Resh, M.D. (2002). Myristoylation as a target for inhibiting HIV assembly: unsaturated fatty acids block viral budding. Proc. Natl Acad. Sci. USA 99, 13037–13042.
Lobo, S., Greentree, W.K., Linder, M.E., and Deschenes, R.J. (2002). Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. J. Biol. Chem. 277, 41268–41273.
Maurer-Stroh, S., Eisenhaber, B., and Eisenhaber, F. (2002a). N-terminal N-myristoylation of proteins: prediction of substrate proteins from amino acid sequence. J. Mol. Biol. 317, 541–557.
Maurer-Stroh, S., Eisenhaber, B., and Eisenhaber, F. (2002b). N-terminal N-myristoylation of proteins: refinement of the sequence motif and its taxon-specific differences. J. Mol. Biol. 317, 523–540.
McCabe, J.B. and Berthiaume, L.G. (1999). Functional roles for fatty acylated amino-terminal domains in subcellular localization. Mol. Biol. Cell 10, 3771–3786.
Melkonian, K.A., Ostermeyer, A.G., Chen, J.Z., Roth, M.G., and Brown, D.A. (1999). Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated. J. Biol. Chem. 274, 3910–3917.
Michaelson, D., Ahearn, I., Bergo, M., Young, S., and Philips, M. (2002). Membrane trafficking of heterotrimeric G proteins via the endoplasmic reticulum and Golgi. Mol. Biol. Cell 13, 3294–3302.
Michaelson, D., Silletti, J., Murphy, G., D’Eustachio, P., Rush, M., and Philips, M.R. (2001). Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell. Biol. 152, 111–126.
Moffett, S., Brown, D.A., and Linder, M.E. (2000). Lipid-dependent targeting of G proteins into rafts. J. Biol. Chem. 275, 2191–2198.
Montixi, C., Langlet, C., Bernard, A.-M., Thimonier, J., Dubois, C., Wurbel, M.-A., Chauvin, J.-P., Pierres, M., and He, H.-T. (1998). Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5348.
Morales, J., Fishburn, C.S., Wilson, ET., and Bourne, H.R. (1998). Plasma Membrane Localization of Gaz Requires Two Signals. Mol. Biol. Cell 9, 1–14.
Mumby, S.M. (1997). Reversible palmitoylation of signaling proteins. Curr. Opin. Cell Biol. 9, 148–154.
Murray, D., Ben-Tal, N., Honig, B., and McLaughlin, S. (1997). Electrostatic interaction of myristoylated proteins with membranes: simple physics, complicated biology. Structure 5, 985–989.
Navarro-Lerida, I., Alvarez-Barrientos, A., Gavilanes, F., and Rodriguez-Crespo, I. (2002). Distance-dependent cellular palmitoylation of de-novo-designed sequences and their translocation to plasma membrane subdomains. J. Cell Sci. 115, 3119–3130.
Okamoto, T., Schlegel, A., Schereer, P.E., and Lisanti, M.P. (1998). Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane. J. Biol. Chem. 273, 5419–5422.
Ono, A. and Freed, E.O. (2001). Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proc. Natl. Acad. Sci. USA 98, 13925–13930.
Peitzsch, R.M. and McLaughlin, S. (1993). Binding of Acylated Peptides and Fatty Acids to Phospholipid Vesicles: Pertinance to Myristoylated Proteins. Biochemistry 32, 10436–10443.
Pepinsky, R.B., Zeng, C., Wen, D., Rayhorn, R, and Baker, D.P.e.a. (1998). Identification of a Palmitic Acid modified form of Human Sonic hedgehog. J. Biol. Chem. 273, 14037–14045.
Peseckis, S.M., Deichaite, I., and Resh, M.D. (1993). Iodinated Fatty Acids as Probes for Myristate Processing and Function. J. Biol. Chem. 268, 5107–5114.
Pierce, S.K. (2002). Lipid rafts and B-cell activation. Nat. Rev. Immunol. 2, 96–105.
Pike, L.J. and Casey, L. (2002). Cholesterol levels modulate EGF receptor-mediated signaling by altering receptor function and trafficking. Biochemistry 41, 10315–10322.
Porter, JA, Young, K.E, and Beachy, P.A. (1996). Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development. Science 274, 255–259.
Prior, I.A. and Hancock, J.F. (2001). Compartmentalization of Ras Proteins. J. Cell Sci. 114, 1603–1608.
Prior, I.A., Harding, A., Yan, J., Sluimer, J., Parton, R.G., and Hancock, J.F. (2001). GTPdependent segregation of H-ras from lipid rafts is required for biological activity. Nat. Cell Biol. 3, 368–375.
Resh, M.D. (1994). Myristylation and Palmitylation of Src Family Members: The Fats of the Matter. Cell 76, 411–413.
Resh, M.D. (1999). Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim. Biophys. Acta 1451, 1–16.
Robbins, S.M., Quintrell, N.A., and Bishop, J.M. (1995). Myristoylation and Differential Palmitoylation of the HCK Protein Tyrosine Kinases Govern Their Attachment to Membranes and Association with Caveolae. Mol. Cell. Biol. 15, 3507–3515.
Robinson, L.J., Busconi, L., and Michel, T. (1995). Agonist-modulated Palmitoylation of Endothelial Nitric Oxide Synthase. J. Biol. Chem. 270, 995–998.
Roth, A.R., Feng, Y., Chen, L., and Davis, N.G. (2002). The yeast DHC cysteine-rich domain protein Akrlp is a palmitoyl transferase. J. Cell Biol. 159, 23–28.
Rousso, I., Mixon, M.G., Chen, B.K., and Kim, P.S. (2000). Palmitoylation of the HIV-1 envelope glycoprotein is critical for viral infectivity. Proc. Natl. Acad. Sci. USA 97, 13523–13525.
Roy, M.O., Leventis, R., and Silvius, J.R. (2000). Mutational and biochemical analysis of plasma membrane targeting mediated by the farnesylated, polybasic carboxy terminus of K-ras4B. Biochemistry 39, 8298–8307.
Schade, A.E. and Levine, A.D. (2002). Lipid raft heterogeneity in human peripheral blood T lymphoblasts: a mechanism for regulating the initiation of TCR signal transduction. J. Immunol. 168, 2233–9.
Scheiffele, P., Roth, M.G., and Simons, K. (1997). Interaction of influenza virus haemagglutinin with sphingolipid-cholesterol membrane domains via its transmembrane domain. EMBO J. 16, 5501–5508.
Schroeder, H., Leventis, R., Shahinian, S., Walton, P.A., and Silvius, J.R. (1996). Lipid-modified, Cysteinyl-containing Peptides of Diverse Structure are Efficiently S-Acylated at the Plasma Membrane of Mammalian Cells. J. Cell Biol. 134, 647–660.
Shahinian, S. and Silvius, J.R. (1995). Doubly lipid-modified protein sequence motifs exhibit long lived anchorage to lipid bilayer membranes. Biochemistry 34, 3813–3822.
Shenoy-Scaria, A.M., Dietzen, D.J., Kwong, J., Link, D.C., and Lublin, D.M. (1994). Cysteine-3 of Src Family Protein Tyrosine Kinases Determines Palmitoylation and Localization in Caveolae. J. Cell Biol. 126, 353–363.
Silvius, J.R. and L’Heureux, E. (1994). Fluorometric evaluation of the affinities of isoprenylated peptides for lipid bilayers. Biochemistry 33, 3014–3022.
Simons, K. and Ehehalt, R. (2002). Cholesterol, lipid rafts, and disease. J. Clin. Invest. 110, 597–603.
Simons, K. and Toomre, D. (2000). Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39.
Sowa, G., Pypaert, M., and Sessa, W.C. (2001). Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proc. Natl. Acad. Sci. USA 98, 14072–14077.
Sproul, T.W., Malapati, S., Kim, J., and Pierce, S.K. (2000). Cutting edge: B cell antigen receptor signaling occurs outside lipid rafts in immature B cells. J. Immunol. 165, 6020–6023.
Tsui-Pierchala, B.A., Encinas, M., Milbrandt, J., and Johnson, E.M. Jr (2002). Lipid rafts in neuronal signaling and function. Trends Neurosci. 25, 412–417.
Duyl, B.Y., Rijkers, D.T., de Kruijff, B., and Killian, J.A. (2002). Influence of hydrophobic mismatch and palmitoylation on the association of transmembrane alpha-helical peptides with detergent-resistant membranes. FEBS Lett 523, 79–84.
Hof, W. and Resh, M.D. (1997). Rapid plasma membrane anchoring of newly synthesized p59fyn: selective requirment for NH2-terminal myristoylation and palmitoylation at cysteine-3. J. Cell Biol. 136, 1023–1035.
Hof, W. and Resh, M.D. (1999). Dual fatty acylation of p59fyn is required for association with the T-cell receptor zeta chain through phosphotyrosine-SH2 interactions. J. Cell Biol. 145, 377–389.
Wang, J., Arbuzova, A., Hangyas-Mihalyne, G., and McLaughlin, S. (2001). The effector domain of myristoylated alanine-rich C kinase substrate binds strongly to phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 276, 5012–5019.
Webb, Y, Hermida-Matsumoto, L., and Resh, M.D. (2000). Inhibition of protein palmitoylation, raft localization and T cell signaling by 2-bromopalmitate and polyunsaturated fatty acids. J. Biol. Chem. 275, 261–270.
Wolven, A., Okamura, H., Rosenblatt, Y, and Resh, M.D. (1997). Palmitoylation of p59fyn is Reversible and Sufficient for Plasma Membrane Association. Mol. Biol. Cell 8, 1159–1173.
Xavier, R., Brennan, T., Li, Q., McCormack, C., and Seed, B. (1998). Membrane Compartmentation is Required for Efficient T Cell Activation. Immunity 8, 723–732.
Yang, X., Claas, C., Kraeft, S.K., Chen, L.B., Wang, Z., Kreidberg, J.A., and Hemler, M.E. (2002). Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology. Mol. Biol. Cell. 13, 767–81.
Yeh, D. C., Duncan, J. A., Yamashita, S., and Michel, T. (1999). Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca(2 +)- calmodulin. J. Biol. Chem. 274, 33148–33154.
Zacharias, D.A., Violin, J.D., Newton, A.C., and Tsien, R.Y. (2002). Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913–916.
Zhang, H., Seabra, M.C., and Deisenhofer, J. (2000). Crystal structure of Rab geranylgeranyltransferase at 2.0 A resolution. Structure 8, 241–251.
Zhang, W, Irvin, B.J., Trible, R.P., Abraham, R.T., and Samelson, L.E. (1999). Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. Int. Immunol. 11, 943–950.
Zhang, W, Trible, R.P., and Samelson, L.E. (1998). LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246.
Zhou, W, Parent, L.J., Wills, J.W., and Resh, M.D. (1994). Identification of a Membrane Binding Domain within the Amino-Terminal Region of Human Immunodeficiency Virus Type 1 Gag Protein Which Interacts with Acidic Phospholipids. J. Virol. 68, 2556–2569.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer Science+Business Media New York
About this chapter
Cite this chapter
Resh, M.D. (2004). Membrane Targeting of Lipid Modified Signal Transduction Proteins. In: Quinn, P.J. (eds) Membrane Dynamics and Domains. Subcellular Biochemistry, vol 37. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-5806-1_6
Download citation
DOI: https://doi.org/10.1007/978-1-4757-5806-1_6
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4419-3447-5
Online ISBN: 978-1-4757-5806-1
eBook Packages: Springer Book Archive