Membrane Targeting by C1 and C2 Domains

Abstract

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 (1), 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) 1 conserved 1 (C1), PKC conserved 2 (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 (2-6) that contain more exhaustive surveys on the membrane targeting domains. Membrane-Protein InteractionsThe 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 A 2 (PLA 2 ) have shown that their membrane binding surfaces are composed of cationic, aliphatic, and aromatic residues (7). 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 (8). Aromatic residues, particularly Trp, which has a preference for the waterlipid interface (9), play a pivotal role in binding to zwitterionic PC membranes (7, 10) by affecting both membrane association and dissociation steps (8). A priori, the physicochemical principles learned from these in vitro membrane 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. Structure, Function, and Occurrence of C1 DomainsThe C1 domain (ϳ50 amino acids) is a cysteine-rich compact structure that contains five short ␤ strands, a short ␣-helix, and two zinc ions (Fig. 2) (11, 12). The C1 domain was first identified as the interaction site for DAG and phorbol ester in PK...

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Specific protein kinase C isoforms as transducers and modulators of insulin signaling

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