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119  structures 543  species 5  interactions 23398  sequences 644  architectures

Family: C2 (PF00168)

Summary: C2 domain

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C2 domain Edit Wikipedia article

C2 domain
C2dom.png
The C2-domain of C.absonum α-toxin (PDB 1OLP). β-strands are shown in yellow. Co-ordinated Calcium ions are in cyan
Identifiers
Symbol C2
Pfam PF00168
InterPro IPR000008
SMART C2
PROSITE PDOC00380
SCOP 1qas
SUPERFAMILY 1qas
OPM superfamily 47
OPM protein 1ugk
CDD cd00030
Phosphoinositide 3-kinase C2
PDB 1e8x EBI.jpg
Structure of phosphoinositide 3-kinase.[1]
Identifiers
Symbol PI3K_C2
Pfam PF00792
InterPro IPR002420
SMART PI3K_C2
PROSITE PDOC50004
SCOP 1e8x
SUPERFAMILY 1e8x
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]

Coupling with other domains[edit]

C2 domains are frequently found coupled to enzymatic domains; for example, the C2 domain in PTEN, brings the phosphatase domain into contact with the 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. In addition to this, 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[edit]

The C2 domain is currently only known from eukaryotes. 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]

Lipid selectivity[edit]

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[4] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding[5] and in membrane targeting processes such as subcellular localisation.

3D structure[edit]

3D structure of C2 domains has been reported,[6] the domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key.[6] 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[edit]

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;

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ a b 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. 

External links[edit]

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Literature references

  1. 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


External database links

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 (that bind phorbol esters and diacylglycerol) (see PROSITEDOC) and the protein kinase catalytic domain (see PROSITEDOC). 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.

Gene Ontology

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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 9 members:

Aida_C2 B9-C2 C2 CC2D2AN-C2 CEP76-C2 DOCK-C2 NT-C2 PI3K_C2 PTEN_C2

Alignments

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(382)
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Representative proteomes NCBI
(21474)
Meta
(315)
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(3560)
RP35
(5729)
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(9404)
RP75
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  Seed
(382)
Full
(23398)
Representative proteomes NCBI
(21474)
Meta
(315)
RP15
(3560)
RP35
(5729)
RP55
(9404)
RP75
(13594)
Alignment:
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  Seed
(382)
Full
(23398)
Representative proteomes NCBI
(21474)
Meta
(315)
RP15
(3560)
RP35
(5729)
RP55
(9404)
RP75
(13594)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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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.

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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 View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: none
Type: Domain
Author: Sonnhammer ELL
Number in seed: 382
Number in full: 23398
Average length of the domain: 86.10 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 17.18 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 4.5
Trusted cut-off 20.9 6.1
Noise cut-off 20.8 -1000000.0
Model length: 85
Family (HMM) version: 25
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Species distribution

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Interactions

There are 5 interactions for this family. More...

PI-PLC-X PLA2_B PI-PLC-Y EF-hand_like C2

Structures

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 119 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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