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. Co-ordinated Calcium ions are in cyan

Identifiers

Symbol

C2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Phosphoinositide 3-kinase C2

Structure of phosphoinositide 3-kinase.^[1]

Identifiers

Symbol

PI3K_C2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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

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. 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

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^[5] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding^[6] and in membrane targeting processes such as subcellular localisation.

3D structure

3D structure of C2 domains has been reported,^[7] the domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key.^[7] 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". Mol. 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 (2015). "Superdomain in the protein structure hierarchy: the case of PTP-C2". Protein Science 24: 874–82. doi:10.1002/pro.2664. 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.
^ ^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

Phosphoinositide 3-kinase C2 family in Pfam
UMich Orientation of Proteins in Membranes families/superfamily-47 - Orientations of C2 domains in membranes (OPM)

v t e Protein domains

BAR BIR BZIP CARD C1 C2 DED ENTH FYVE HEAT Kringle LIM LRR NACHT PAS PDZ Pyrin PH PX SH2 SH3 SUN TRIO WD40 zinc finger

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C2 domain Provide feedback

No Pfam abstract.

Literature references

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:	PI3K_C2 B9-C2 NT-C2 PTEN_C2 C2-C2_1 DOCK-C2 CEP76-C2
Similarity to PfamA using HHSearch:	PI3K_C2

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 (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

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Molecular function

protein binding (GO:0005515)

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 11 members:

Aida_C2 B9-C2 C2 C2-C2_1 CC2D2AN-C2 CEP76-C2 DOCK-C2 NT-C2 PI3K_C2 PTEN_C2 Spond_N

Alignments

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...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
UniProt: alignment generated by searching the UniProtKB sequence database using the family HMM
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

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You can see the alignments as HTML or in three different sequence viewers:

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PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.

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Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

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 (261)	Full (39609)	Representative proteomes				UniProt (66264)	NCBI (134780)	Meta (338)
	Seed (261)	Full (39609)	RP15 (8412)	RP35 (17459)	RP55 (28555)	RP75 (35826)	UniProt (66264)	NCBI (134780)	Meta (338)
Jalview	View	View	View	View	View	View	View	View	View
HTML	View
PP/heatmap	₁

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (261)	Full (39609)	Representative proteomes				UniProt (66264)	NCBI (134780)	Meta (338)
	Seed (261)	Full (39609)	RP15 (8412)	RP35 (17459)	RP55 (28555)	RP75 (35826)	UniProt (66264)	NCBI (134780)	Meta (338)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (261)	Full (39609)	Representative proteomes				UniProt (66264)	NCBI (134780)	Meta (338)
	Seed (261)	Full (39609)	RP15 (8412)	RP35 (17459)	RP55 (28555)	RP75 (35826)	UniProt (66264)	NCBI (134780)	Meta (338)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	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.

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

Author:

Sonnhammer ELL, Eberhardt R

Number in seed:

261

Number in full:

39609

Average length of the domain:

106.00 aa

Average identity of full alignment:

18 %

Average coverage of the sequence by the domain:

20.55 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.9	8.1
Trusted cut-off	20.9	8.1
Noise cut-off	20.8	8.0

Model length:

103

Family (HMM) version:

28

Download:

download the raw HMM for this family

Species distribution

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Colour assignments

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

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order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

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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.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

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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Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

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.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

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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Interactions

There are 15 interactions for this family. More...

PLA2_B EF-hand_like PI-PLC-Y PI-PLC-X FGF SH2 S_100 PI-PLC-Y S_100 PI-PLC-X C2 FGF EF-hand_10 FYVE_2 EF-hand_like

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 187 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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Family: C2 (PF00168)

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