C2Protein kinase C conserved region 2 (CalB)
|SMART accession number:||SM00239|
|Description:||Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.|
|Interpro abstract (IPR000008):||The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C (that bind phorbol esters and diacylglycerol) and the protein kinase catalytic domain . Regions with significant homology [(PUBMED:7559667)] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding [(PUBMED:8253763)] and in membrane targetting processes such as subcellular localisation. |
The 3D structure of the C2 domain of synaptotagmin has been reported [(PUBMED:7697723)], the domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key [(PUBMED:7697723)]. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel beta sandwich.
|GO function:||protein binding (GO:0005515)|
Click on the following links for more information.
- Evolution (species in which this domain is found)
Click on to expand nodes. To display all proteins with a C2 domain in a specific node, click on it.
This tree shows only several representative species. The complete taxonomic breakdown of all proteins with C2 domain is also avaliable.
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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
- Cellular role (predicted cellular role)
Cellular role: signalling
Binding / catalysis: calcium-binding, phospholipid-binding, inositol polyphosphate-binding, membrane-binding
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Rizo J, Sudhof TC
- C2-domains, structure and function of a universal Ca2+-binding domain.
- J Biol Chem. 1998; 273: 15879-82
- Hurley JH, Newton AC, Parker PJ, Blumberg PM, Nishizuka Y
- Taxonomy and function of C1 protein kinase C homology domains.
- Protein Sci. 1997; 6: 477-80
- Display abstract
C1 domains are compact alpha/beta structural units of about 50 amino acids which tightly bind two zinc ions. These domains were first discovered as the loci of phorbol ester and diacylglycerol binding to conventional protein kinase C isozymes, which contain 2 C1 domains (C1A and C1B) in their N-terminal regulatory regions. We present a comprehensive list of 54 C1 domains occurring singly or doubly in 34 different proteins. Many C1 domains and C1 domain-containing proteins bind phorbol esters, but many others do not. By combining analysis of 54 C1 domain sequences with information from previously reported solution and crystal structure determinations and site-directed mutagenesis, profiles are derived and used to classify C1 domains. Twenty-six C1 domains fit the profile for phorbol-ester binding and are termed "typical." Twenty-eight other domains fit the profile for the overall C1 domain fold but do not fit the profile for phorbol ester binding, and are termed "atypical." Proteins containing typical C1 domains are predicted to be regulated by diacylglycerol, whereas those containing only atypical domains are not.
- Puls A, Schmidt S, Grawe F, Stabel S
- Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein.
- Proc Natl Acad Sci U S A. 1997; 94: 6191-6
- Display abstract
The atypical protein kinase C (PKC) member PKC-zeta has been implicated in several signal transduction pathways regulating differentiation, proliferation or apoptosis of mammalian cells. We report here the identification of a cytoplasmic and membrane-associated protein that we name zeta-interacting protein (ZIP) and that interacts with the regulatory domain of PKC-zeta but not classic PKCs. The structural motifs in ZIP include a recently defined ZZ zinc finger as a potential protein binding module, two PEST sequences and a novel putative protein binding motif with the consensus sequence YXDEDX5SDEE/D. ZIP binds to the pseudosubstrate region in the regulatory domain of PKC-zeta and is phosphorylated by PKC-zeta in vitro. ZIP dimerizes via the same region that promotes binding to PKC-zeta suggesting a competitive situation between ZIP:ZIP and ZIP:PKC-zeta complexes. In the absence of PKC-zeta proper subcellular localization of ZIP is impaired and we show that intracellular targeting of ZIP is dependent on a balanced interaction with PKC-zeta. Taking into account the recent isolation of ZIP by others in different contexts we propose that ZIP may function as a scaffold protein linking PKC-zeta to protein tyrosine kinases and cytokine receptors.
- Nalefski EA, Falke JJ
- The C2 domain calcium-binding motif: structural and functional diversity.
- Protein Sci. 1996; 5: 2375-90
- Display abstract
The C2 domain is a Ca(2+)-binding motif of approximately 130 residues in length originally identified in the Ca(2+)-dependent isoforms of protein kinase C. Single and multiple copies of C2 domains have been identified in a growing number of eukaryotic signalling proteins that interact with cellular membranes and mediate a broad array of critical intracellular processes, including membrane trafficking, the generation of lipid-second messengers, activation of GTPases, and the control of protein phosphorylation. As a group, C2 domains display the remarkable property of binding a variety of different ligands and substrates, including Ca2+, phospholipids, inositol polyphosphates, and intracellular proteins. Expanding this functional diversity is the fact that not all proteins containing C2 domains are regulated by Ca2+, suggesting that some C2 domains may play a purely structural role or may have lost the ability to bind Ca2+. The present review summarizes the information currently available regarding the structure and function of the C2 domain and provides a novel sequence alignment of 65 C2 domain primary structures. This alignment predicts that C2 domains form two distinct topological folds, illustrated by the recent crystal structures of C2 domains from synaptotagmin 1 and phosphoinositide-specific phospholipase C-delta 1, respectively. The alignment highlights residues that may be critical to the C2 domain fold or required for Ca2+ binding and regulation.
- Ponting CP, Parker PJ
- Extending the C2 domain family: C2s in PKCs delta, epsilon, eta, theta, phospholipases, GAPs, and perforin.
- Protein Sci. 1996; 5: 162-6
- Display abstract
Various membrane lipid metabolites, generated by phospholipases C and D (PLCs, PLDs), are known to regulate the activities of protein kinases C (PKCs) and GTP-ase activating proteins (GAPs) in a range of cellular processes. Conventional Ca(2+)-dependent PKCs (alpha, beta I, beta II, and gamma), PLCs and various GAPs are all known to contain copies of a phospholipid-binding domain, termed C2 or CalB. Here we recognize that C2 domains are also present in "new" Ca(2+)-independent PKCs (delta, epsilon, eta, and theta), other kinases, a eukaryotic PLD, the breakpoint cluster region (BCR) gene product, and two further GAPS. Twenty-two previously unrecognized C2 domain sequences are presented, which include a single copy in the mammalian poreforming proteins, perforin.
- Shao X, Davletov BA, Sutton RB, Sudhof TC, Rizo J
- Bipartite Ca2+-binding motif in C2 domains of synaptotagmin and protein kinase C.
- Science. 1996; 273: 248-51
- Display abstract
C2 domains are found in many proteins involved in membrane traffic or signal transduction. Although C2 domains are thought to bind calcium ions, the structural basis for calcium binding is unclear. Analysis of calcium binding to C2 domains of synaptotagmin I and protein kinase C-beta by nuclear magnetic resonance spectroscopy revealed a bipartite calcium-binding motif that involves the coordination of two calcium ions by five aspartate residues located on two separate loops. Sequence comparisons indicated that this may be a widely used calcium-binding motif, designated here as the C2 motif.
- Li C, Ullrich B, Zhang JZ, Anderson RG, Brose N, Sudhof TC
- Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins.
- Nature. 1995; 375: 594-9
- Display abstract
Synaptotagmins (Syts) are brain-specific Ca2+/phospholipid-binding proteins. In hippocampal synapses, Syt I is essential for fast Ca(2+)-dependent synaptic vesicle exocytosis but not for Ca(2+)-independent exocytosis. In vertebrates and invertebrates, Syt may therefore participate in Ca(2+)-dependent synaptic membrane fusion, either by serving as the Ca2+ sensor in the last step of fast Ca(2+)-triggered neurotransmitter release, or by collaborating with an additional Ca2+ sensor. While Syt I binds Ca2+ (refs 10, 11), its phospholipid binding is triggered at lower calcium concentrations (EC50 = 3-6 microM) than those required for exocytosis. Furthermore, Syts bind clathrin-AP2 with high affinity, indicating that they may play a general role in endocytosis rather than being confined to a specialized function in regulated exocytosis. Here we resolve this apparent contradiction by describing four Syts, three of which (Syt VI, VII and VIII) are widely expressed in non-neural tissues. All Syts tested share a common domain structure, with a cytoplasmic region composed of two C2 domains that interacts with clathrin-AP2 (Kd = 0.1-1.0 nM) and with neural and non-neural syntaxins. The first C2 domains of Syt I, II, III, V and VII, but not of IV, VI or VIII, bind phospholipids with a similar Ca(2+)-concentration dependence (EC50 = 3-6 microM). The same C2 domains also bind syntaxin as a function of Ca2+ but the Ca(2+)-concentration dependence of Syt I, II and V (> 200 microM) differs from that of Syt III and VII (< 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
- Sutton RB, Davletov BA, Berghuis AM, Sudhof TC, Sprang SR
- Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold.
- Cell. 1995; 80: 929-38
- Display abstract
C2 domains are regulatory sequence motifs that occur widely in nature. Synaptotagmin I, a synaptic vesicle protein involved in the Ca2+ regulation of exocytosis, contains two C2 domains, the first of which acts as a Ca2+ sensor. We now describe the three-dimensional structure of this C2 domain at 1.9 A resolution in both the Ca(2+)-bound and Ca(2+)-free forms. The C2 polypeptide forms an eight-stranded beta sandwich constructed around a conserved four-stranded motif designated as a C2 key. Ca2+ binds in a cup-shaped depression between two polypeptide loops located at the N- and C-termini of the C2-key motif.
- Brose N, Petrenko AG, Sudhof TC, Jahn R
- Synaptotagmin: a calcium sensor on the synaptic vesicle surface.
- Science. 1992; 256: 1021-5
- Display abstract
Neurons release neurotransmitters by calcium-dependent exocytosis of synaptic vesicles. However, the molecular steps transducing the calcium signal into membrane fusion are still an enigma. It is reported here that synaptotagmin, a highly conserved synaptic vesicle protein, binds calcium at physiological concentrations in a complex with negatively charged phospholipids. This binding is specific for calcium and involves the cytoplasmic domain of synaptotagmin. Calcium binding is dependent on the intact oligomeric structure of synaptotagmin (it is abolished by proteolytic cleavage at a single site). These results suggest that synaptotagmin acts as a cooperative calcium receptor in exocytosis.
- Perin MS, Fried VA, Mignery GA, Jahn R, Sudhof TC
- Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C.
- Nature. 1990; 345: 260-3
- Display abstract
Neurotransmitters are released at synapses by the Ca2(+)-regulated exocytosis of synaptic vesicles, which are specialized secretory organelles that store high concentrations of neurotransmitters. The rapid Ca2(+)-triggered fusion of synaptic vesicles is presumably mediated by specific proteins that must interact with Ca2+ and the phospholipid bilayer. We now report that the cytoplasmic domain of p65, a synaptic vesicle-specific protein that binds calmodulin contains an internally repeated sequence that is homologous to the regulatory C2-region of protein kinase C (PKC). The cytoplasmic domain of recombinant p65 binds acidic phospholipids with a specificity indicating an interaction of p65 with the hydrophobic core as well as the headgroups of the phospholipids. The binding specificity resembles PKC, except that p65 also binds calmodulin, placing the C2-regions in a context of potential Ca2(+)-regulation that is different from PKC. This is a novel homology between a cellular protein and the regulatory domain of protein kinase C. The structure and properties of p65 suggest that it may have a role in mediating membrane interactions during synaptic vesicle exocytosis.
- Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the C2 domain.
Protein Disease Perforin-1 (P14222) (SMART) OMIM:170280: Hemophagocytic lymphohistiocytosis, familial, 2
- Metabolism (metabolic pathways involving proteins which contain this domain)
Click the image to view the interactive version of the map in iPath
% proteins involved KEGG pathway ID Description 10.12 map04070 Phosphatidylinositol signaling system 7.26 map00562 Inositol phosphate metabolism 7.19 map04020 Calcium signaling pathway 4.46 map04730 Long-term depression 3.93 map04370 VEGF signaling pathway 3.93 map04650 Natural killer cell mediated cytotoxicity 3.86 map04310 Wnt signaling pathway 3.86 map04720 Long-term potentiation 3.86 map04916 Melanogenesis 3.86 map04540 Gap junction 3.60 map04010 MAPK signaling pathway 3.33 map04670 Leukocyte transendothelial migration 3.33 map05214 Glioma 3.33 map05223 Non-small cell lung cancer 3.33 map04012 ErbB signaling pathway 3.13 map04530 Tight junction 2.93 map04912 GnRH signaling pathway 2.33 map04510 Focal adhesion 2.00 map04664 Fc epsilon RI signaling pathway 1.60 map04120 Ubiquitin mediated proteolysis 1.53 map00564 Glycerophospholipid metabolism 1.13 map04620 Toll-like receptor signaling pathway 1.00 map05120 Epithelial cell signaling in Helicobacter pylori infection 1.00 map00565 Ether lipid metabolism 0.87 map05050 Dentatorubropallidoluysian atrophy (DRPLA) 0.80 map05220 Chronic myeloid leukemia 0.73 map04350 TGF-beta signaling pathway 0.73 map04360 Axon guidance 0.60 map04140 Regulation of autophagy 0.60 map00590 Arachidonic acid metabolism 0.60 map00592 alpha-Linolenic acid metabolism 0.60 map04940 Type I diabetes mellitus 0.60 map00591 Linoleic acid metabolism 0.53 map05040 Huntington's disease 0.47 map00260 Glycine, serine and threonine metabolism 0.40 map05222 Small cell lung cancer 0.40 map05213 Endometrial cancer 0.40 map04662 B cell receptor signaling pathway 0.40 map05212 Pancreatic cancer 0.40 map04630 Jak-STAT signaling pathway 0.40 map04810 Regulation of actin cytoskeleton 0.40 map05210 Colorectal cancer 0.40 map04210 Apoptosis 0.40 map04910 Insulin signaling pathway 0.40 map05215 Prostate cancer 0.40 map04150 mTOR signaling pathway 0.40 map04660 T cell receptor signaling pathway 0.40 map05211 Renal cell carcinoma 0.40 map05221 Acute myeloid leukemia 0.40 map04930 Type II diabetes mellitus 0.40 map05218 Melanoma 0.40 map04914 Progesterone-mediated oocyte maturation 0.13 map00380 Tryptophan metabolism 0.07 map00632 Benzoate degradation via CoA ligation
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with C2 domain which could be assigned to a KEGG orthologous group, and not all proteins containing C2 domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
- Structure (3D structures containing this domain)
3D Structures of C2 domains in PDB
PDB code Main view Title 1a25 C2 domain from protein kinase c (beta) 1bci C2 domain of cytosolic phospholipase a2, nmr, minimized average structure 1bdy C2 domain from protein kinase c delta 1byn Solution structure of the calcium-bound first c2-domain of synaptotagmin i 1cjy Human cytosolic phospholipase a2 1djg Phosphoinositide-specific phospholipase c-delta1 from rat complexed with lanthanum 1djh Phosphoinositide-specific phospholipase c-delta1 from rat complexed with barium 1dji Phosphoinositide-specific phospholipase c-delta1 from rat complexed with calcium 1djw Phosphoinositide-specific phospholipase c-delta1 from rat complexed with inositol-2-methylene-1,2-cyclic- monophosphonate 1djx Phosphoinositide-specific phospholipase c-delta1 from rat complexed with inositol-1,4,5-trisphosphate 1djy Phosphoinositide-specific phospholipase c-delta1 from rat complexed with inositol-2,4,5-trisphosphate 1djz Phosphoinositide-specific phospholipase c-delta1 from rat complexed with inositol-4,5-bisphosphate 1dqv Crystal structure of synaptotagmin iii c2a/c2b 1dsy C2 domain from protein kinase c (alpha) complexed with ca2+ and phosphatidylserine 1gmi Structure of the c2 domain from novel protein kinase c epsilon 1k5w Three-dimensional structure of the synaptotagmin 1 c2b- domain: synaptotagmin 1 as a phospholipid binding machine 1qas 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta 1 1qat 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta complex with samarium (iii) chloride 1rh8 Three-dimensional structure of the calcium-free piccolo c2a- domain 1rlw Calcium-phospholipid binding domain from cytosolic phospholipase a2 1rsy Structure of the first c2-domain of synaptotagmin i: a novel ca2+(slash)phospholipid binding fold 1tjm Crystallographic identification of sr2+ coordination site in synaptotagmin i c2b domain 1tjx Crystallographic identification of ca2+ coordination sites in synaptotagmin i c2b domain 1ugk Solution structure of the first c2 domain of synaptotagmin iv from human fetal brain (kiaa1342) 1uov Calcium binding domain c2b 1uow Calcium binding domain c2b 1v27 Solution structure of the first c2 domain of rim2 1w15 Rat synaptotagmin 4 c2b domain in the presence of calcium 1w16 Rat synaptotagmin 4 c2b domain in the absence of calcium 1wfj C2 domain-containing protein from putative elicitor- responsive gene 1yrk The c2 domain of pkc is a new phospho-tyrosine binding domain 2b3r Crystal structure of the c2 domain of class ii phosphatidylinositide 3-kinase c2 2bwq Crystal structure of the rim2 c2a-domain at 1.4 angstrom resolution 2chd Crystal structure of the c2a domain of rabphilin-3a 2cjs Structural basis for a munc13-1 dimeric - munc13-1 - rim heterodimer switch: c2-domains as versatile protein- protein interaction modules 2cjt Structural basis for a munc13-1 dimeric - munc13-1 - rim heterodimer switch: c2-domains as versatile protein- protein interaction modules 2cm5 Crystal structure of the c2b domain of rabphilin 2cm6 Crystal structure of the c2b domain of rabphilin3a 2d8k Solution structure of the first c2 domain of synaptotagmin vii 2dmg Solution structure of the third c2 domain of kiaa1228 protein 2dmh Solution structure of the first c2 domain of human myoferlin 2enp Solution structure of the first c2 domain from human b/k protein 2enq Solution structure of the c2 domain from human pi3-kinase p110 subunit alpha 2ep6 Solution structure of the second c2 domain from human mctp2 protein 2fju Activated rac1 bound to its effector phospholipase c beta 2 2fk9 Human protein kinase c, eta 2isd Phosphoinositide-specific phospholipase c-delta1 from rat 2jqz Solution structure of the c2 domain of human smurf2 2k3h Structural determinants for ca2+ and pip2 binding by the c2a domain of rabphilin-3a 2k45 C2a domain of synaptototagmin i solution structure in the fgf-1-c2a binary complex: key component in the fibroblast growthfactor non-classical pathway 2k4a Fgf-1-c2a binary complex structure: a key component in the fibroblast growthfactor non-classical pathway 2k8m S100a13-c2a binary complex structure 2nq3 Crystal structure of the c2 domain of human itchy homolog e3 ubiquitin protein ligase 2nsq Crystal structure of the c2 domain of the human e3 ubiquitin-protein ligase nedd4-like protein 2q3x The rim1alpha c2b domain 2r83 Crystal structure analysis of human synaptotagmin 1 c2a-c2b 2rd0 Structure of a human p110alpha/p85alpha complex 2uzp Crystal structure of the c2 domain of human protein kinase c gamma. 2zkm Crystal structure of phospholipase c beta 2 3b7y Crystal structure of the c2 domain of the e3 ubiquitin- protein ligase nedd4 3bxj Crystal structure of the c2-gap fragment of syngap 3f00 Crystal structure of synaptotagmin i c2a domain with cu(ii) 3f01 Crystal structure of synaptotagmin i c2a domain with cu(ii) 3f04 Crystal structure of synaptotagmin i c2a domain 3f05 Crystal structure of synaptotagmin i c2a domain with mn(ii) 3fbk Crystal structure of the c2 domain of the human regulator of g-protein signaling 3 isoform 6 (rgp3), northeast structural genomics consortium target hr5550a 3fdw Crystal structure of a c2 domain from human synaptotagmin- like protein 4 3gpe Crystal structure analysis of pkc (alpha)-c2 domain complexed with ca2+ and ptdins(4,5)p2 3hhm Crystal structure of p110alpha h1047r mutant in complex with nish2 of p85alpha and the drug wortmannin 3hiz Crystal structure of p110alpha h1047r mutant in complex with nish2 of p85alpha 3jzy Crystal structure of human intersectin 2 rhogef domain 3rpb The c2b-domain of rabphilin: structural variations in a janus-faced domain
- Links (links to other resources describing this domain)
PFAM C2 INTERPRO IPR000008 PROSITE C2_DOMAIN_2