Summary: Phosphoinositide 3-kinase C2
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C2 domain Edit Wikipedia article
The C2-domain of C.absonum α-toxin (PDB 1OLP). β-strands are shown in yellow. Co-ordinated Calcium ions are in cyan
|Phosphoinositide 3-kinase C2|
Structure of phosphoinositide 3-kinase.
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 β-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. 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.
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.
3D structure of C2 domains has been reported, 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". Mol. Cell. 6 (4): 909–19. doi:10.1016/S1097-2765(05)00089-4. PMID 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 (1–2): 18–30. doi:10.1016/j.gene.2010.08.006. PMC . PMID 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): 3861–75. doi:10.4161/cc.22068. PMC . PMID 22983010.
- Haynie DT, Xue B (2015). "Superdomain in the protein structure hierarchy: the case of PTP-C2". Protein Science. 24: 874–82. doi:10.1002/pro.2664. PMC . PMID 25694109.
- Hata Y, Hofmann K, Sudhof TC, Brose N (1995). "Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins". J. Biol. Chem. 270 (42): 25273–80. doi:10.1074/jbc.270.42.25273. PMID 7559667.
- Davletov BA, Sudhof TC (1993). "A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding". J. Biol. Chem. 268 (35): 26386–90. PMID 8253763.
- Sutton RB, Davletov BA, Berghuis AM, Sprang SR, Sudhof TC (1995). "Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold". Cell. 80 (6): 929–38. doi:10.1016/0092-8674(95)90296-1. PMID 7697723.
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Phosphoinositide 3-kinase C2 Provide feedback
Phosphoinositide 3-kinase region postulated to contain a C2 domain. Outlier of PF00168 family.
Internal database links
|Similarity to PfamA using HHSearch:||C2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002420
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate 4,5-bisphonate (PI(4,5) P2 or PIP2) at the 3-position of the inositol ring, and thus generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which, in turns, initiates a vast array of signaling events. PI3Ks can be grouped into three classes based on their domain organisation. Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit of either the p85 type (associated with the class IA p110 isoforms p110alpha, p110beta or p110delta) or the p101 type (associated with the class IB p110 isoform p110gamma). Common to all catalytic subunits are an N-terminal adaptor-binding domain (ABD) that binds to p85, a Ras- binding domain (RBD), a putative membrane-binding domain (C2), a helical domain of unknown function, and a kinase catalytic domain. Class II PI3Ks lack the ABD domain and are distinguished by a carboxy terminal C2 domain. Class III enzymes lack the ABD and RBD domains [PUBMED:17626883, PUBMED:18079394, PUBMED:20081827, PUBMED:10580505].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Seed source:||Alignment kindly provided by SMART|
|Author:||SMART, Griffiths-Jones SR|
|Number in seed:||17|
|Number in full:||1745|
|Average length of the domain:||140.80 aa|
|Average identity of full alignment:||22 %|
|Average coverage of the sequence by the domain:||12.88 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
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Unmapped species names
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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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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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.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 PI3K_C2 domain has been found. There are 140 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 seqence.
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