C2 domain

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.{{cite journal | vauthors = Haynie DT, Xue B | title = Superdomains in the protein structure hierarchy: The case of PTP-C2 | journal = Protein Science | volume = 24 | issue = 5 | pages = 874–82 | date = May 2015 | pmid = 25694109 | pmc = 4420535 | doi = 10.1002/pro.2664 }} 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).

The C2 domain is currently only known from eukaryotes and the prokaryote Clostridium perfringens where it is part of the alpha-toxin.{{Cite journal|last1=Naylor|first1=Claire E.|last2=Eaton|first2=Julian T.|last3=Howells|first3=Angela|last4=Justin|first4=Neil|last5=Moss|first5=David S.|last6=Titball|first6=Richard W.|last7=Basak|first7=Ajit K.|date=August 1998|title=Structure of the key toxin in gas gangrene|journal=Nature Structural & Molecular Biology|volume=5|issue=8|pages=738–746|doi=10.1038/1447|pmid=9699639|s2cid=21000585|issn=1545-9993}} Over 17 distinct clades of C2 domains have been identified. 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.

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 homology{{cite journal | vauthors = Brose N, Hofmann K, Hata Y, Südhof TC | title = Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins | journal = The Journal of Biological Chemistry | volume = 270 | issue = 42 | pages = 25273–80 | date = October 1995 | pmid = 7559667 | doi = 10.1074/jbc.270.42.25273 | doi-access = free }} to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding{{cite journal | vauthors = Davletov BA, Südhof TC | title = A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding | journal = The Journal of Biological Chemistry | volume = 268 | issue = 35 | pages = 26386–90 | date = December 1993 | doi = 10.1016/S0021-9258(19)74326-9 | doi-access = free | pmid = 8253763 }} 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.{{cite journal | vauthors = Nalefski EA, Wisner MA, Chen JZ, Sprang SR, Fukuda M, Mikoshiba K, Falke JJ | title = C2 domains from different Ca2+ signaling pathways display functional and mechanistic diversity | journal = Biochemistry | volume = 40 | issue = 10 | pages = 3089–100 | date = March 2001 | pmid = 11258923 | pmc = 3862187 | doi=10.1021/bi001968a}}

The domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key.{{cite journal | vauthors = Sutton RB, Davletov BA, Berghuis AM, Südhof TC, Sprang SR | title = Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold | journal = Cell | volume = 80 | issue = 6 | pages = 929–38 | date = March 1995 | pmid = 7697723 | doi = 10.1016/0092-8674(95)90296-1 | s2cid = 18981505 | doi-access = free }} 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;

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

{{reflist}}

• [https://web.archive.org/web/20081004162200/http://pfam.sanger.ac.uk/family?entry=PF00792 Phosphoinositide 3-kinase C2 family in Pfam]
• {{UMichOPM|families|superfamily|47}} - Orientations of C2 domains in membranes (OPM)

{{Protein domains}}

Category:Peripheral membrane proteins

Category:Protein domains

Category:Protein superfamilies