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C2 Domain C2 Domain Proteins

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C2 Domain C2 Domain Proteins C C2 Domain Introduction ▶ C2 Domain Proteins Comprising approximately 130 amino acids, the C2 ▶ Calcium-Binding Proteins, Overview domain was first identified as a conserved domain of the calcium-dependent protein kinases C (PKC). 233 C2 domains are predicted in 127 human proteins, making the C2 domain, after the pleckstrin homology C2 Domain Proteins (PH) domain, the second most abundant lipid-binding domain found in eukaryotic proteins. Since the original Thomas A. Leonard identification of the C2 domain as the calcium sensor Max F. Perutz Laboratories, Vienna, Austria in PKC, both Ca2+-binding and non-Ca2+-binding C2 domains have been characterized in a wide variety of lipid signal transduction enzymes and membrane- Synonyms trafficking proteins. By sensing the lipid microenvi- ronments within cells, C2 domains, coupled to 2nd conserved domain of protein kinase C; C2 domain; a variety of effector domains, spatially and temporally Calcium-binding region; CBR; Endocytosis; regulate both lipid second messenger signaling and Exocytosis; Intracellular signaling; LH2 domain; membrane fusion events. Lipoxygenase homology domain; Membrane traffick- To date, there are structures available for 31 C2 ing; Second messenger signaling; Signal transduction; domains from 24 proteins; the C2 fold is a b-sandwich Vesicle fusion of two four-stranded antiparallel b-sheets (Fig. 1). Three loops at the top of the domain and four at the bottom connect the b-strands. Topologically, the C2 Definition domain comes in two flavors that differ in the connec- tivity of their b-strands: By fusing the N- and C-termini C2 domain proteins are proteins containing the sec- and cutting the loop between strands b1 and b2, type ond conserved domain of protein kinase C. The C2 I topology can be converted into type II. A third C2 domain is an all-beta domain, consisting of a beta- topology, called the LH2 domain, will be discussed sandwich of two antiparallel four-stranded beta later in more detail. Despite adopting two different sheets. C2 domains are found in a wide range of topologies, the C2 domains of synaptotagmin (C2A; both enzymatic and non-enzymatic proteins type I) and phospholipase C-d1 (PLC-d1) (type II) involved in signal transduction and membrane differ by a root mean square deviation of only 1.4 A˚ . trafficking. It is, as yet, unclear why C2 domains exist in two V.N. Uversky et al. (eds.), Encyclopedia of Metalloproteins, DOI 10.1007/978-1-4614-1533-6, # Springer Science+Business Media New York 2013 C 310 C2 Domain Proteins C2 Domain Proteins, 3 3 Fig. 1 C2 domain structure 1 1 and topology. The structures 2 2 1 of type I (I, synaptotagmin), 2 3 type II (II, PKCe), and type III (III, Clostridium perfringens alpha toxin LH2 domain) 4 8 topology C2 domains are 3 2 5 2 illustrated in the upper panels. 6 4 4 5 3 6 5 The beta sandwich fold is 2 7 1 3 1 8 1 8 7 highlighted by the coloring of 6 the two antiparallel b-sheets in 7 blue and orange. Strand b1of the type I topology C2 domain and the equivalent b-strands in type II and type III C2 domains are colored in red to orient the I II III viewer. The Ca2+-binding (LH2) regions (CBRs) are shown in green, together with the bound 1 3 1 3 1 3 Ca2+ ions, represented as spheres. The corresponding topology diagrams (middle 4 3 67 3 2 56 3 2 58 panels) illustrate the 2 2 2 connectivity of the b-strands. The strand numbers, colors, C and annotation of the topology NC diagrams correspond to the structural representations 5 2 1 8 4 1 8 7 4 1 6 7 shown in the upper panels. Numbers in circles reflect the CBRs. The topologically N C N distinct CBR3 of the LH2 domain is highlighted with synaptotagmin PI3Kα lipoxygenases yellow circles. Below each rabphilin PLCs β, δ pancreatic lipases topology diagram and RIM1α cPLA2 bacterial alpha toxins structure is a list of PKCs α, β, γ PKCs δ, ε, η, θ representative proteins RASAL Nedd4 containing the respective PTEN topology C2 domain perforin distinct topologies, but it has been speculated that the Ca2+-Binding C2 Domains topology could influence the relative orientation of a C2 domain with respect to its neighboring domains; Intracellular signaling elicited by external stimuli is in type I C2 domains (synaptotagmin, PKCbII), the N- often mediated by an increase in cytosolic Ca2+ and C-termini are on the top surface of the domain, concentration. Release of intracellular stores of Ca2+ whereas in type II C2 domains (PLC-d1, cPLA2), the in response to agonist activation of G protein–coupled termini are at the bottom. Despite a high degree of receptors or growth factor activation of receptor tyro- structural conservation in the core b-sandwich of the sine kinases recruits C2 domain–containing proteins to C2 domain, there is low sequence conservation the membrane. The recruitment of effectors to the between the C2 domains of different proteins. The membrane by small molecules, which diffuse freely type I C2 domains of synaptotagmin and PKCbII in the cytosol, enables signals originating at the mem- exhibit only 30% sequence identity over 126 equiva- brane to be propagated in a rapid and synchronous lent residues, while the type II C2 domains of PLC-d1 manner. The involvement of C2 domains in metal ion and PLA2 are only 18% sequence identical (Nalefski binding was first postulated on the basis that the and Falke 1996; Rizo and Sudhof 1998). calcium-independent PKCs apparently lacked this C2 Domain Proteins 311 C domain (in fact, they do contain a non-Ca2+-binding domains of PKCs a and bII, cPLA2, and PLCd1. In C2 domain with an alternate topology, but this was not synaptotagmin I, the coordination sphere of the bound discovered until later). Subsequent studies on PKCs Ca2+ ion is incomplete, explaining the low affinity of and other C2 domain–containing proteins such as this site. It has been speculated that anionic phospho- synaptotagmins and cytosolic phospholipase A2 lipids may fill unsatisfied coordination sites at site III, (cPLA2) identified the C2 domain as being responsible increasing the affinity for Ca2+.Ca2+ is observed at site for Ca2+-dependent membrane binding. Ca2+ binding I in cPLA2 and PLCd1, but not at sites II and III. C is mediated exclusively by residues in the loops Instead, a second binding site, site IV, is created by connecting the b-strands at the top of the domain the juxtaposition of two conserved aspartates in CBR1. (e.g., PKCbII, Fig. 1 I); these loops were thus desig- While equivalent aspartates exist in CBR1 of nated the Ca2+-binding regions (CBRs), although this synaptotagmin and PKCs a and bII, Ca2+ is not designation is somewhat misleading as a number of C2 observed at this site. Structurally, there is no imped- domains do not bind calcium (e.g., PKCe, Fig. 1 II). ance to Ca2+ binding at site IV, and variations in Ca2+ Of those that do, however, both C2 domain topologies occupancy may be due to its observation in the absence mediate binding to calcium in identical ways, since the of membranes. Only lanthanum (La3+) was observed at circular permutation that converts the two topologies site II of PLCd1, despite an identical arrangement of does not affect the CBRs. The Ca2+ binding sites are the Ca2+-binding residues to that found in primarily formed by aspartate side chains that serve as synaptotagmin 1. It seems likely, however, that Ca2+ bidentate ligands for two or three Ca2+ ions (Nalefski is bound at site II in the presence of phospholipids. and Falke 1996; Rizo and Sudhof 1998). The intrinsic In cPLA2, conservative substitutions of calcium- affinities for Ca2+ at each of the binding sites vary chelating aspartates in CBR3 probably reduce the dramatically between C2 domains and are up to affinity for Ca2+ at site III, though since the binding three orders of magnitude higher in the presence of of Ca2+ is cooperative and since site II is not occupied phospholipids. Half-maximal binding of C2 domains in the absence of phospholipids, it is conceivable to lipid vesicles typically occurs at 5-50 mM; Ca2+ has that all of these C2 domains contain a total of four been shown to simultaneously increase the association Ca2+-binding sites. The structures of Ca2+-free and 2+ 2+ rate constant (ka) of C2 domains with membranes, Ca -bound C2 domains show that Ca does and decrease the dissociation rate constant, (kd). Elec- not induce a substantial conformational change, trostatic interactions mediated by Ca2+ primarily suggesting that the C2 domain acts as a calcium sensor accelerate the rate of association with anionic mem- in the cell. NMR studies have shown that Ca2+ induces branes, while penetration of the hydrophobic core of a stabilization and reduction in conformational the membrane has been proposed as the primary mech- flexibility in the CBRs. In this way, Ca2+ binding by anism by which dissociation from the membrane is the C2 domain differs markedly from another class of slowed. Ca2+ ions have been observed in four distinct Ca2+ effector domains, EF-hands, in which binding of positions in isolated C2 domain structures, but in the a single Ca2+ ion to a contiguous helix-turn-helix motif absence of structural information on lipid binding for induces a conformational change that exposes hydro- the majority of these domains, it is unclear whether all phobic surfaces. Ca2+ causes an increase in the thermal four sites are capable of playing functionally equiva- denaturation temperature and confers resistance to lent roles. However, the structural arrangement of the proteolytic degradation of the C2A domain of Ca2+-binding motifs provides an unambiguous expla- synaptotagmin I.
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