C2 domain

Pfam_box
Symbol = C2
Name = C2 domain

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width =200
caption = The C2-domain of "C.absonum" α-toxin (PDB 1OLP). β-strands are shown in yellow. Co-ordinated Calcium ions are in cyan
Pfam= PF00168
InterPro= IPR000008
SMART= C2
PROSITE = PDOC00380
SCOP = 1qas
TCDB =
OPM family= 47
OPM protein= 1ugk
PDB=PDB3|1a25B:173-260 PDB3|1dsyA:173-260 PDB3|3rpbA:557-645PDB3|1rh8A:4654-4752 PDB3|1dqvA:314-400 PDB3|1bynA:158-244PDB3|1ugkA:170-258 PDB3|1uovA:289-377 PDB3|1k5wA:289-377PDB3|1tjxA:289-377 PDB3|1uowA:289-377 PDB3|1tjmA:289-377PDB3|1w15A:304-392 PDB3|1w16A:304-392 PDB3|2b3rA:1574-1662PDB3|1v27A:822-913 PDB3|2bwqA:760-851 PDB3|1bci :20-106PDB3|1cjyA:20-106 PDB3|1rlw :20-106 PDB3|1wfjA:6-87PDB3|1djyA:631-720 PDB3|1djhB:631-720 PDB3|1djgB:631-720PDB3|1qatB:631-720 PDB3|1djiB:631-720 PDB3|2isdB:631-720PDB3|1djxA:631-720 PDB3|1qasB:631-720 PDB3|1djzB:631-720PDB3|1djwB:631-720 PDB3|1gmiA:8-99 PDB3|1wfmA:189-259

A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. It is composed of 8 β-sheets, forming a beta-sandwich motif, and co-ordinates 2 or 3 calcium ions, which bind in an indentation formed by the first and final loops of the domain, on the membrane binding face.

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 membrane where it can dephosphorylate its substrate, 3,4,5 tetraphospho-inositol, 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).

C2 domains are also found in clostridial alpha toxins, where they are used to bring the catalytic phospholipase domain into contact with the plasma membrane, conferring the toxic activity on the protein. These are the only known examples of C2 domains in prokaryotes.

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 [http://www.expasy.org/cgi-bin/prosite-search-ac?PDOC00379 PDOC00379] ) and the protein kinase catalytic domain (see [http://www.expasy.org/cgi-bin/prosite-search-ac?PDOC00100 PDOC00100] ). Regions with significant homologycite journal |author=Hata Y, Hofmann K, Sudhof TC, Brose N |title=Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins |journal=J. Biol. Chem. |volume=270 |issue=42 |pages=25273–25280 |year=1995 |pmid=7559667 |doi=10.1074/jbc.270.42.25273] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid bindingcite journal |author=Davletov BA, Sudhof TC |title=A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding |journal=J. Biol. Chem. |volume=268 |issue=35 |pages=26386–26390 |year=1993 |pmid=8253763] and in membrane targeting processes such as subcellular localisation.

3D structure

3D structure of C2 domains has been reportedcite journal |author=Sutton RB, Davletov BA, Berghuis AM, Sprang SR, Sudhof TC |title=Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold |journal=Cell |volume=80 |issue=6 |pages=929–938 |year=1995 |pmid=7697723 |doi=10.1016/0092-8674(95)90296-1] , 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; C8orfK23; 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; KIAA0528; KIAA1228; KIAA1957;
LOC392742; 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; sytdep;

References

External links

* [http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC00380 C2 domain] in PROSITE
* [http://pfam.sanger.ac.uk/family?entry=PF00168 C2 domain family in Pfam]
* [http://pfam.sanger.ac.uk/family?entry=PF00792 Phosphoinositide 3-kinase C2 family in Pfam]
* - Orientations of C2 domains in membranes (OPM)