Summary: C2 domain
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C2 domain Edit Wikipedia article
|SCOP2||1qas / SCOPe / SUPFAM|
|Phosphoinositide 3-kinase C2|
|SCOP2||1e8x / SCOPe / SUPFAM|
A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 Î²-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by the first and final loops of the domain, on the membrane binding face. Many other C2 domain families don't have calcium binding activity.
Coupling with other domains
C2 domains are frequently found coupled to enzymatic domains; for example, the C2 domain in PTEN, brings the phosphatase domain into contact with the plasma membrane, where it can dephosphorylate its substrate, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), without removing it from the membrane - which would be energetically very costly. PTEN consists of two domains, a protein tyrosine phosphatase domain and a C2 domain. This domain pair constitutes a superdomain, a heritable unit that is found in various proteins in fungi, plants and animals. In addition, phosphatidylinositol 3-kinase (PI3-kinase), an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring, also uses a C2 domain to bind to the membrane (e.g. 1e8w PDB entry).
The C2 domain is currently only known from eukaryotes and the prokaryote Clostridium perfringens where it is part of the alpha-toxin. Over 17 distinct clades of C2 domains have been identified. Most C2 families can be traced back to basal eukaryotic species indicating an early diversification before the last eukaryotic common ancestor (LECA). Only the PKC-C2 domain family contains conserved calcium-binding residues, suggesting the typical calcium-dependent membrane interaction is a derived feature limited in PKC-C2 domains.
Calcium and Lipid selectivity
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) (see PDOC00379) and the protein kinase catalytic domain (see PDOC00100). Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targeting processes such as subcellular localisation. Although most C2 domains interact with the membrane (phospholipids) in a Ca2+-dependent manner, some C2 domains can interact with the membrane without binding to Ca2+. Similarly, C2 domains have been evolved to have different specificities for lipids. Many C2 domains such as synaptotagmin C2A, bind to anionic phospholipids (PS or PIP2 containing phospholipids). However, other C2 domains such as cPLA2-Î± C2 domain bind to zwitterionic lipids (e.g. PC). This diversity and selectivity in Ca2+ and lipid binding suggest that C2 domains are evolved to have different functions.
The domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key. 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.
Human proteins containing C2 domain
ABR; BAIAP3; BCR; C2CD2; C2CD3; CADPS; CADPS2; CAPN5; CAPN6; CC2D1A; CC2D1B; CPNE1; CPNE2; CPNE3; CPNE4; CPNE5; CPNE6; CPNE7; CPNE8; CPNE9; DAB2IP; DOC2A; DOC2B; DYSF; ESYT1; ESYT3; FAM62A; FAM62B; FAM62C; FER1L3; FER1L5; HECW1; HECW2; ITCH; ITSN1; ITSN2; MCTP1; MCTP2; MTAC2D1; NEDD4; NEDD4L; NEDL1; OTOF; PCLO; PIK3C2A; PIK3C2B; PIK3C2G; PLA2G4A; PLA2G4B; PLA2G4D; PLA2G4E; PLA2G4F; PLCB1; PLCB2; PLCB3; PLCB4; PLCD1; PLCD3; PLCD4; PLCE1; PLCG1; PLCG2; PLCH1; PLCH2; PLCL1; PLCL2; PLCZ1; PRF1; PRKCA; PRKCB1; PRKCE; PRKCG; PRKCH; RAB11FIP1; RAB11FIP2; RAB11FIP5; RASA1; RASA2; RASA3; RASA4; RASAL1; RASAL2; RGS3; RIMS1; RIMS2; RIMS3; RIMS4; RPGRIP1; RPGRIP1L; RPH3A; SGA72M; SMURF1; SMURF2; SYNGAP1; SYT1; SYT10; SYT11; SYT12; SYT13; SYT14; SYT14L; SYT15; SYT16; SYT17; SYT2; SYT3; SYT4; SYT5; SYT6; SYT7; SYT8; SYT9; SYTL1; SYTL2; SYTL3; SYTL4; SYTL5; TOLLIP; UNC13A; UNC13B; UNC13C; UNC13D; WWC2; WWP1; WWP2; PTEN
- Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL (October 2000). "Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine". Molecular Cell. 6 (4): 909â€“19. doi:10.1016/S1097-2765(05)00089-4. PMIDÂ 11090628.
- Zhang D, Aravind L (December 2010). "Identification of novel families and classification of the C2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes". Gene. 469 (1â€“2): 18â€“30. doi:10.1016/j.gene.2010.08.006. PMCÂ 2965036. PMIDÂ 20713135.
- Zhang D, Aravind L (October 2012). "Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment". Cell Cycle. 11 (20): 3861â€“75. doi:10.4161/cc.22068. PMCÂ 3495828. PMIDÂ 22983010.
- Haynie DT, Xue B (May 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. 24 (5): 874â€“82. doi:10.1002/pro.2664. PMCÂ 4420535. PMIDÂ 25694109.
- Naylor, Claire E.; Eaton, Julian T.; Howells, Angela; Justin, Neil; Moss, David S.; Titball, Richard W.; Basak, Ajit K. (August 1998). "Structure of the key toxin in gas gangrene". Nature Structural & Molecular Biology. 5 (8): 738â€“746. doi:10.1038/1447. ISSNÂ 1545-9993. PMIDÂ 9699639. S2CIDÂ 21000585.
- Brose N, Hofmann K, Hata Y, SÃ¼dhof TC (October 1995). "Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins". The Journal of Biological Chemistry. 270 (42): 25273â€“80. doi:10.1074/jbc.270.42.25273. PMIDÂ 7559667.
- Davletov BA, SÃ¼dhof TC (December 1993). "A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding". The Journal of Biological Chemistry. 268 (35): 26386â€“90. PMIDÂ 8253763.
- Nalefski EA, Wisner MA, Chen JZ, Sprang SR, Fukuda M, Mikoshiba K, Falke JJ (March 2001). "C2 domains from different Ca2+ signaling pathways display functional and mechanistic diversity". Biochemistry. 40 (10): 3089â€“100. doi:10.1021/bi001968a. PMCÂ 3862187. PMIDÂ 11258923.
- Sutton RB, Davletov BA, Berghuis AM, SÃ¼dhof TC, Sprang SR (March 1995). "Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold". Cell. 80 (6): 929â€“38. doi:10.1016/0092-8674(95)90296-1. PMIDÂ 7697723. S2CIDÂ 18981505.
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C2 domain Provide feedback
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Internal database links
|SCOOP:||C2-C2_1 CEP76-C2 Haspin_kinase MUN NT-C2 Peptidase_M50 PI3K_C2|
|Similarity to PfamA using HHSearch:||PI3K_C2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000008
The C2 domain is a Ca 2+ -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 and the protein kinase catalytic domain [ PUBMED:22453964 ]. 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 Ca 2+ -binding loops are located at the end of an 8 stranded antiparallel beta sandwich.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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This superfamily includes C2 domains and C2-like domains.
The clan contains the following 18 members:Aida_C2 Anillin B9-C2 C2 C2-C2_1 CC2D2AN-C2 CEP76-C2 DOCK-C2 IcmF_C MNNL NT-C2 PI3K_C2 PTEN_C2 pYEATS RPGR1_C SPATA6 Spond_N YEATS
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|Author:||Sonnhammer ELL , Eberhardt R|
|Number in seed:||258|
|Number in full:||183893|
|Average length of the domain:||106.40 aa|
|Average identity of full alignment:||19 %|
|Average coverage of the sequence by the domain:||19.67 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||33|
|Download:||download the raw HMM for this family|
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The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the C2 domain has been found. There are 339 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.