Summary: C2 domain
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C2 domain Edit Wikipedia article
| C2 domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 The C2-domain of C.absonum α-toxin (PDB 1OLP). β-strands are shown in yellow, α-helices in red, loops in green. Co-ordinated Calcium ions are in cyan. | |||||||||
| Identifiers | |||||||||
| Symbol | C2 | ||||||||
| Pfam | PF00168 | ||||||||
| InterPro | IPR000008 | ||||||||
| SMART | C2 | ||||||||
| PROSITE | PDOC00380 | ||||||||
| SCOPe | 1qas / SUPFAM | ||||||||
| OPM superfamily | 45 | ||||||||
| OPM protein | 1ugk | ||||||||
| CDD | cd00030 | ||||||||
| |||||||||
| Phosphoinositide 3-kinase C2 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 Structure of phosphoinositide 3-kinase.[1] | |||||||||||
| Identifiers | |||||||||||
| Symbol | PI3K_C2 | ||||||||||
| Pfam | PF00792 | ||||||||||
| InterPro | IPR002420 | ||||||||||
| SMART | PI3K_C2 | ||||||||||
| PROSITE | PDOC50004 | ||||||||||
| SCOPe | 1e8x / SUPFAM | ||||||||||
| CDD | cd08380 | ||||||||||
| |||||||||||
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.[2][3]
Contents
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.[4] 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).
Evolution
The C2 domain is currently only known from eukaryotes and the procaryote Clostridium perfringens where it is part of the alpha-toxin.[5] Over 17 distinct clades of C2 domains have been identified.[2][3] 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.[2]
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[6] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding[7] 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-α 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.[8]
3D structure
The domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key [9]. 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
References
- ^ 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): 909–19. doi:10.1016/S1097-2765(05)00089-4. PMID 11090628.
- ^ a b c 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 2965036. PMID 20713135.
- ^ a b 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 3495828. PMID 22983010.
- ^ Haynie DT, Xue B (May 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. 24 (5): 874–82. doi:10.1002/pro.2664. PMC 4420535. PMID 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): 738–746. doi:10.1038/1447. ISSN 1545-9993. PMID 9699639.
- ^ Brose N, Hofmann K, Hata Y, Südhof 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): 25273–80. doi:10.1074/jbc.270.42.25273. PMID 7559667.
- ^ Davletov BA, Südhof 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): 26386–90. PMID 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): 3089–100. doi:10.1021/bi001968a. PMC 3862187. PMID 11258923.
- ^ Sutton RB, Davletov BA, Berghuis AM, Südhof TC, Sprang SR (March 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.
External links
- Phosphoinositide 3-kinase C2 family in Pfam[permanent dead link]
- UMich Orientation of Proteins in Membranes families/superfamily-47 - Orientations of C2 domains in membranes (OPM)
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
C2 domain Provide feedback
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Literature references
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Ponting CP, Parker PJ; , Protein Sci 1996;5:162-166.: Extending the C2 domain family: C2s in PKCs delta, epsilon, eta, theta, phospholipases, GAPs, and perforin. PUBMED:8771209 EPMC:8771209
Internal database links
| SCOOP: | C2-C2_1 CEP76-C2 NT-C2 PI3K_C2 |
| Similarity to PfamA using HHSearch: | PI3K_C2 C2-C2_1 |
External database links
| HOMSTRAD: | C2 |
| PRINTS: | PR00360 |
| PROSITE: | PDOC00380 |
| SCOP: | 1qas |
This tab holds annotation information from the InterPro database.
InterPro entry 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 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 Ca2+-binding loops are located at the end of an 8 stranded antiparallel beta sandwich.
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan C2 (CL0154), which has the following description:
This superfamily includes C2 domains and C2-like domains.
The clan contains the following 16 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 RPGR1_C Spond_N YEATSAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
| Seed (260) |
Full (107921) |
Representative proteomes | UniProt (167988) |
NCBI (309594) |
Meta (325) |
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| RP15 (13958) |
RP35 (38872) |
RP55 (74422) |
RP75 (110069) |
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| PP/heatmap | 1 | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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| Seed (260) |
Full (107921) |
Representative proteomes | UniProt (167988) |
NCBI (309594) |
Meta (325) |
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|---|---|---|---|---|---|---|---|---|---|
| RP15 (13958) |
RP35 (38872) |
RP55 (74422) |
RP75 (110069) |
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| Raw Stockholm | |||||||||
| Gzipped | |||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Swissprot_feature_table |
| Previous IDs: | none |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Sonnhammer ELL  , Eberhardt R
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| Number in seed: | 260 |
| Number in full: | 107921 |
| Average length of the domain: | 106.40 aa |
| Average identity of full alignment: | 18 % |
| Average coverage of the sequence by the domain: | 19.87 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 103 | ||||||||||||
| Family (HMM) version: | 31 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
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Interactions
There are 15 interactions for this family. More...
PI-PLC-Y C2 PLA2_B S_100 EF-hand_10 SH2 FGF PI-PLC-X EF-hand_like FYVE_2 EF-hand_like S_100 FGF PI-PLC-Y PI-PLC-XStructures
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 285 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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