Membrane Targeting by C1 and C2 Domains

protein kinase C phospholipase A2 cytosolic phospholipase A2 gastrin-releasing peptide fragment green fluorescent protein diacylglycerol phosphatidylcholine phosphatidylserine phorbol 12-myristate 13-acetate Many peripheral proteins involved in cell signaling translocate to different cell membranes in response to specific cell stimuli. Because cellular functions and regulation of these proteins depend on their specific subcellular localization (1Teruel M.N. Meyer T. Cell. 2000; 103: 181-184Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar), understanding the mechanisms of membrane targeting is of great importance. The membrane targeting of diverse peripheral proteins is mediated by a limited number of membrane-targeting domains, including protein kinase C (PKC)1conserved 1 (C1), PKC conserved2 (C2), and pleckstrin homology domains. Recent structural and functional studies of individual membrane targeting domains as well as the peripheral proteins harboring these domains have provided new insights into the molecular mechanisms underlying the specific subcellular targeting and activation of peripheral proteins. This review summarizes the recent progress in our understanding of the mechanisms of C1 and C2 domain-mediated membrane targeting, with an emphasis on the correlation between the membrane binding properties of the C1 and C2 domains and the peripheral proteins containing these domains and their subcellular targeting behaviors. There are several excellent reviews (2Nalefski E.A. Falke J.J. Protein Sci. 1996; 5: 2375-2390Crossref PubMed Scopus (687) Google Scholar, 3Rizo J. Sudhof T.C. J. Biol. Chem. 1998; 273: 15879-15882Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 4Ron D. Kazanietz M.G. FASEB J. 1999; 13: 1658-1676Crossref PubMed Scopus (552) Google Scholar, 5Rebecchi M.J. Scarlata S. Annu. Rev. Biophys. Biomol. Struct. 1998; 27: 503-528Crossref PubMed Scopus (249) Google Scholar, 6Hurley J.H. Misra S. Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 49-79Crossref PubMed Scopus (225) Google Scholar) that contain more exhaustive surveys on the membrane targeting domains. The membrane binding of peripheral proteins involves different types of interactions (Fig. 1) that depend upon the physicochemical properties of both membrane and protein. Membranes of different cellular compartments have different compositions of bulk lipids that can modulate membrane targeting of proteins either by providing unique microenvironments or by producing specific lipid metabolites, such as diacylglycerol (DAG) and phosphoinositides, that function as second messengers. Extensive structural and mutational studies of phospholipases A2(PLA2) have shown that their membrane binding surfaces are composed of cationic, aliphatic, and aromatic residues (7Gelb M.H. Cho W. Wilton D.C. Curr. Opin. Struct. Biol. 1999; 9: 428-432Crossref PubMed Scopus (116) Google Scholar). A recent study by surface plasmon resonance analysis indicated that cationic residues primarily accelerate the association of protein to anionic membrane surfaces, whereas aliphatic residues mainly slow the membrane dissociation by penetrating into the hydrophobic core of the membrane (8Stahelin R.V. Cho W. Biochemistry. 2001; 40: 4672-4678Crossref PubMed Scopus (145) Google Scholar). Aromatic residues, particularly Trp, which has a preference for the water-lipid interface (9Yau W.M. Wimley W.C. Gawrisch K. White S.H. Biochemistry. 1998; 37: 14713-14718Crossref PubMed Scopus (824) Google Scholar), play a pivotal role in binding to zwitterionic PC membranes (7Gelb M.H. Cho W. Wilton D.C. Curr. Opin. Struct. Biol. 1999; 9: 428-432Crossref PubMed Scopus (116) Google Scholar, 10Han S.K. Kim K.P. Koduri R. Bittova L. Munoz N.M. Leff A.R. Wilton D.C. Gelb M.H. Cho W. J. Biol. Chem. 1999; 274: 11881-11888Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar) by affecting both membrane association and dissociation steps (8Stahelin R.V. Cho W. Biochemistry. 2001; 40: 4672-4678Crossref PubMed Scopus (145) Google Scholar). A priori, the physicochemical principles learned from these in vitromembrane binding studies should allow the prediction of the subcellular targeting behaviors of peripheral proteins, provided that the subcellular targeting is driven mainly by membrane-protein interactions. The C1 domain (∼50 amino acids) is a cysteine-rich compact structure that contains five short β strands, a short α-helix, and two zinc ions (Fig. 2) (11Hommel U. Zurini M. Luyten M. Struct. Biol. 1994; 1: 383-387Crossref PubMed Scopus (137) Google Scholar, 12Zhang G. Kazanietz M.G. Blumberg P.M. Hurley J.H. Cell. 1995; 81: 917-924Abstract Full Text PDF PubMed Scopus (595) Google Scholar). The C1 domain was first identified as the interaction site for DAG and phorbol ester in PKCs (13Nishizuka Y. Nature. 1988; 334: 661-665Crossref PubMed Scopus (3532) Google Scholar). In conventional (α, βI, βII, and γ) and novel (δ, ε, θ, and η) PKCs, the C1 domain occurs in a tandem repeat (C1A and C1B). C1 domains have been subsequently found in other proteins with diverse functions, including protein kinase D (PKD/PKCµ), chimaerin, Ras-GRP, Unc-13, Munc13 isoforms, DAG kinases, and Raf (4Ron D. Kazanietz M.G. FASEB J. 1999; 13: 1658-1676Crossref PubMed Scopus (552) Google Scholar). In general, C1 domains show a high degree of amino acid sequence homology. Some C1 domains, including those found in atypical PKCs (ζ and ι/λ), however, do not bind lipids due to minor sequence variations and might be involved in protein-protein interactions (4Ron D. Kazanietz M.G. FASEB J. 1999; 13: 1658-1676Crossref PubMed Scopus (552) Google Scholar). This review will focus mainly on the C1 domains involved in DAG and phorbol ester binding. Structural (12Zhang G. Kazanietz M.G. Blumberg P.M. Hurley J.H. Cell. 1995; 81: 917-924Abstract Full Text PDF PubMed Scopus (595) Google Scholar) and mutation (14Kazanietz M.G. Bustelo X.R. Barbacid M. Kolch W. Mischak H. Wong G. Pettit G.R. Bruns J.D. Blumberg P.M. J. Biol. Chem. 1994; 269: 11590-11594Abstract Full Text PDF PubMed Google Scholar) studies of PKCδ-C1B have defined the phorbol ester/DAG binding pocket. The polar binding pocket is located at the tip of the molecule and is surrounded by aliphatic and aromatic residues, which are adjoined by a ring of cationic residues in the middle part of the molecule (Fig. 2). A NMR study of PKCγ-C1B (15Xu R.X. Pawelczyk T. Xia T.-H. Brown S.C. Biochemistry. 1997; 36: 10709-10717Crossref PubMed Scopus (121) Google Scholar) and a monolayer penetration study of PKCα (16Medkova M. Cho W. J. Biol. Chem. 1999; 274: 19852-19861Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) showed that the hydrophobic residues of the C1 domain penetrate the membrane for DAG/phorbol ester binding. The phorbol ester binding seals the polar surface in the binding pocket and thereby generates a contiguous hydrophobic surface (12Zhang G. Kazanietz M.G. Blumberg P.M. Hurley J.H. Cell. 1995; 81: 917-924Abstract Full Text PDF PubMed Scopus (595) Google Scholar), which in turn greatly enhances the stability of the C1-membrane complex (17Mosior M. Newton A.C. J. Biol. Chem. 1995; 270: 25526-25533Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 18Medkova M. Cho W. Biochemistry. 1998; 37: 4892-4900Crossref PubMed Scopus (78) Google Scholar). Further mutational studies of PKCα showed that clustered cationic residues in the C1A domain are involved in nonspecific electrostatic interactions with anionic phospholipids (19Bittova L. Stahelin R.V. Cho W. J. Biol. Chem. 2001; 276: 4218-4226Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). In agreement with this finding, the isolated C1 domain repeat (i.e. C1A + C1B) of PKCα exhibits little head group specificity among anionic phospholipids while discriminating against PC (16Medkova M. Cho W. J. Biol. Chem. 1999; 274: 19852-19861Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Together these studies on PKC C1 domains have led to a model for C1 domain-membrane interactions illustrated in Fig. 2. In this model, cationic residues accelerate the initial adsorption of the C1 domain to the anionic membrane surfaces and properly position the C1 domain at the membrane surface. Then, the hydrophobic tip of the domain penetrates the membrane to bind DAG that is partially in the membrane of hydrophobic Because C1 domains with the hydrophobic are to protein in a be for the C1 domain-mediated membrane In the of conventional PKCs, has been shown that C1 domains are at the and to DAG or phorbol membrane binding (19Bittova L. Stahelin R.V. Cho W. J. Biol. Chem. 2001; 276: 4218-4226Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The C1 domains of J. S. K. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, J. J. Sci. U. S. 1994; PubMed Scopus Google Scholar), Cell. Biol. 1998; PubMed Scopus Google Scholar), and M.J. Blumberg P.M. Mischak H. S. K. Kazanietz M.G. Sci. U. S. 1999; PubMed Scopus Google Scholar) have been shown to the cellular membrane targeting of the peripheral proteins in response to DAG and phorbol Because analysis of their interactions with membranes has been is not the mechanisms of C1 domain-mediated membrane binding of these peripheral proteins are to that of and novel PKCs contain two of C1 domains. studies on conventional PKC the of J. Biol. Chem. Full Text PDF PubMed Google Scholar) and ester binding U. Y. Y. R. Y. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar), that C1 domain is involved in DAG/phorbol ester binding and PKC A recent study of isolated C1A and domains of PKCs that domains have for phorbol C1A domains K. K. Y. H. H. H. U. J. Chem. 1998; Scopus Google Scholar). The was the C1A and domains of which show high correlation was between the phorbol ester of C1A and domains and their in phorbol activation K. S. T. Blumberg P.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), the that the of C1 domains mainly from their different for phorbol however, was shown that C1A and domains of PKCα play an role in cellular membrane in response to phorbol 12-myristate 13-acetate their phorbol ester K. Blumberg P.M. 1998; Google Scholar). correlation between the DAG of C1 domains and their in PKC activation has not been A of binding studies of PKCα indicated that PKCα contains two phorbol ester binding with high and and that DAG and phorbol bind to the two with J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, J.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The that DAG and phorbol might have different C1A was by the that the C1A domain is involved in the binding and activation of PKCα (16Medkova M. Cho W. J. Biol. Chem. 1999; 274: 19852-19861Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). more studies are to these complex interactions of the C1 domains of PKC with their The subcellular targeting of isolated C1 domains and PKC in response to DAG and phorbol has been in with green fluorescent protein proteins Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Y. Y. J. Biol. 1997; PubMed Scopus Google Scholar, S. Y. M. H. U. Cell. Biol. 1998; PubMed Google Scholar, M.N. Meyer T. J. Biol. 1998; PubMed Scopus Google Scholar, D. S. K. Blumberg P.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, D. S. Blumberg P.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. S. J. 1999; PubMed Scopus Google Scholar). to membrane in response to in K. Y. Y. J. Biol. 1997; PubMed Scopus Google Scholar). In and and domains showed the to membrane in response to or DAG M.N. Meyer T. J. Biol. 1998; PubMed Scopus Google Scholar). is the with J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, K.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), S. Y. M. H. U. Cell. Biol. 1998; PubMed Google Scholar), PKCα K. S. J. 1999; PubMed Scopus Google Scholar), and T. D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) shown to translocate to membrane in response to or In the of PKC the of of proteins not their studies showed that whereas and other hydrophobic phorbol the initial of to the hydrophobic DAG and to translocate to the D. S. K. Blumberg P.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, D. S. Blumberg P.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). cell study and W. in of with a fluorescent phorbol ester the that the subcellular localization of C1 is a of the subcellular targeting of This in turn that the in vitromembrane binding and the subcellular targeting of C1 domain are driven by the to proteins to to the subcellular targeting of domains the binding site is not located in the C1 domains D. FASEB J. 1998; PubMed Scopus Google Scholar) and the show little on C1 domain M.N. Meyer T. J. Biol. 1998; PubMed Scopus Google Scholar, K. S. J. 1999; PubMed Scopus Google Scholar). The C2 domain was first as the site in conventional PKCs (15Xu R.X. Pawelczyk T. Xia T.-H. Brown S.C. Biochemistry. 1997; 36: 10709-10717Crossref PubMed Scopus (121) Google Scholar). A great number of proteins containing the C2 domain have been identified and of are involved in cytosolic phospholipases phospholipase and or membrane and (2Nalefski E.A. Falke J.J. 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This review will mainly with the C2 domains that bind phospholipids in a The of C2 domains are composed of that contain for Structural Sudhof T.C. J. 1996; 273: PubMed Scopus Google Scholar, Sudhof T.C. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, R. M. Nature. 1996; PubMed Scopus Google Scholar, S. J. 1999; PubMed Scopus Google Scholar, S. M. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and binding M. T. K. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Falke J.J. Biochemistry. 1997; 36: PubMed Scopus Google Scholar, L. R. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) have the binding and for several C2 domains. of ions in the membrane targeting of the C2 domain have been The first role of ions is to a between the C2 domain and anionic This model is by an structure of the complex S. 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Biochemistry. 1998; 37: PubMed Scopus Google Scholar), whereas those of PKCα and C2 domain have (16Medkova M. Cho W. J. Biol. Chem. 1999; 274: 19852-19861Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 18Medkova M. Cho W. Biochemistry. 1998; 37: 4892-4900Crossref PubMed Scopus (78) Google Scholar). This that the of a C2 domain to the membrane binding of a peripheral protein on the structural of the particularly on the of other membrane targeting domains in the The subcellular targeting of C2 domains and peripheral proteins, conventional PKCs and has been in different In general, the subcellular localization behaviors of C2 domains are with their in membrane binding C2 domains of conventional PKCs that anionic phospholipids translocate to membrane Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and to the in response to G. S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. 1999; PubMed Scopus Google Scholar). this subcellular localization of isolated C2 domains with that of peripheral proteins harboring the C2 conventional PKCs translocate to the membrane K. Y. Y. J. Biol. 1997; PubMed Scopus Google Scholar, S. Y. M. H. U. Cell. Biol. 1998; PubMed Google Scholar, M.N. Meyer T. J. Biol. 1998; PubMed Scopus Google Scholar, K. S. J. 1999; PubMed Scopus Google Scholar) whereas to the S. T. M. Gelb M.H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). proteins of PKCα and containing the C2 domains of and are to the and J. and W. in is that anionic C2 domains will translocate to membrane and that C2 domains will translocate to the conventional PKCs are by both C1 and however, their subcellular localization is primarily by the subcellular of C1 the C2 domain to the and of Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). recent of and their correlation between the subcellular targeting and in vitromembrane to to the in response to subcellular of correlation with their in membrane binding that the subcellular targeting of these C2 domains is primarily driven by that their membrane binding. Some proteins, including the domain of T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and the domain of J. 1999; PubMed Scopus Google Scholar, S. M. R. H. K. H. G. H. K. W. Sci. U. S. 2000; PubMed Scopus Google Scholar), have C2 In the domain of has been shown to have specific T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and to be for the of J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus (121) Google Scholar). The domain of has been shown to have PC of the of aromatic residues in the and W. in The of peripheral proteins have two membrane targeting domains the of domains is not for their membrane This that their membrane targeting and activation might a of the membrane targeting domains. A of C1 and C2 domains in the membrane localization of PKC was for Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and K.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The interactions between C1 and C2 domains have been for the targeting and regulation of different PKC In the of a anionic in the C1A domain is in the of C1A to the other part of the the C2 domain (19Bittova L. Stahelin R.V. Cho W. J. Biol. Chem. 2001; 276: 4218-4226Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). The the protein in an at the and is by the binding of the C2 domain to in the which in turn to the membrane penetration and DAG binding of the C1A domain and PKC was that the domain of novel PKC with the C1 domain to the J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Further studies will more of interactions in the membrane targeting of peripheral domains. In both protein-protein and membrane-protein the initial of nonspecific driven by and electrostatic is by the of which are by specific interactions (8Stahelin R.V. Cho W. Biochemistry. 2001; 40: 4672-4678Crossref PubMed Scopus (145) Google Scholar, J. Biol. PubMed Scopus Google Scholar). The interactions mainly the association whereas the interactions primarily the dissociation C1 domains, the initial binding is driven by nonspecific electrostatic interactions between cationic residues with bulk anionic the complex is by both hydrophobic interactions between hydrophobic C1 residues and the membrane core and between polar C1 residues and DAG (Fig. 2). the subcellular localization of the C1 domain is primarily by the of DAG and phorbol the bulk lipid of the targeting membrane can the of Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). anionic C2 domains, the initial binding is driven by electrostatic interactions cationic residues, or a of the of specific interactions for complex the binding and Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the other the membrane binding of is driven by interactions between aromatic residues and PC (8Stahelin R.V. Cho W. Biochemistry. 2001; 40: 4672-4678Crossref PubMed Scopus (145) Google Scholar), the binding is due to membrane penetration and the hydrophobic interactions. In with these membrane binding can the membrane localization of in the whereas both C1 and C2 domains are for the membrane localization of conventional PKC Meyer T. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, K.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the C1 the bulk lipid of the membrane is an of localization of the C2 domains. the prediction of subcellular localization of C2 domains on their lipid the lipid compositions of cellular membranes of different to be in this review show that of the of the peripheral proteins harboring C1 and C2 domains can be for by the physicochemical principles that their in vitromembrane binding The subcellular targeting of peripheral proteins containing a targeting domain the membrane binding properties of the whereas that of peripheral proteins with C1 and C2 domains is by the of the domains and the of their The principles learned from these studies should in understanding the subcellular targeting of peripheral proteins containing other membrane targeting domains. Because C1 and C2 domains can with other proteins D. FASEB J. 1998; PubMed Scopus Google Scholar), the subcellular targeting of and proteins might both membrane-protein and protein-protein interactions. protein might play an role in the subcellular targeting of peripheral proteins J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, K.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Further studies are to these cellular studies of peripheral proteins have been mainly on membrane and regulation of signaling peripheral proteins, however, is to the and of peripheral proteins as well as the of their in Recent in and cell should greatly this