| C2 domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 The C2-domain ofC.absonum α-toxin (PDB 1OLP). β-strands are shown in yellow, α-helices in red, loops in green. Co-ordinatedcalcium ions are in cyan. | |||||||||
| Identifiers | |||||||||
| Symbol | C2 | ||||||||
| Pfam | PF00168 | ||||||||
| Pfam clan | CL0154 | ||||||||
| ECOD | 11.2.1 | ||||||||
| InterPro | IPR000008 | ||||||||
| SMART | C2 | ||||||||
| PROSITE | PDOC00380 | ||||||||
| SCOP2 | 1qas /SCOPe /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 | ||||||||||
| Pfam clan | CL0154 | ||||||||||
| ECOD | 11.2.1 | ||||||||||
| InterPro | IPR002420 | ||||||||||
| SMART | PI3K_C2 | ||||||||||
| PROSITE | PDOC50004 | ||||||||||
| SCOP2 | 1e8x /SCOPe /SUPFAM | ||||||||||
| CDD | cd08380 | ||||||||||
| |||||||||||
AC2 domain is aproteinstructural domain involved in targeting proteins tocell membranes. The typical version (PKC-C2) has abeta-sandwich composed of 8β-strands that co-ordinates two or threecalcium 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]
C2 domains are frequently found coupled toenzymatic domains; for example, the C2 domain inPTEN, brings thephosphatase 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, aprotein 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 thatphosphorylatesphosphoinositides on the 3-hydroxyl group of theinositol 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 and the prokaryoteClostridium perfringens where it is part of thealpha-toxin.[5] Over 17 distinct clades of C2 domains have been identified.[2][3] Most C2 families can be traced back tobasal 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]
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) (seePDOC00379) and the protein kinase catalytic domain (seePDOC00100). 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 assynaptotagmin 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]
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.
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;MAP3K20;MCTP1;MCTP2;MTAC2D1;NEDD4;NEDD4L;NEDL1;OTOF;PKN1;PKN2;PKN3;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;PRKCD;PRKCE;PRKCG;PRKCH;PRKCQ;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