A C2 domain is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

structural domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

involved in targeting proteins to

cell membranes The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...

. The typical version (PKC-C2) has a

beta-sandwich Beta-sandwich or β-sandwich domains consisting of 80 to 350 amino acids occur commonly in proteins. They are characterized by two opposing antiparallel beta sheets (β-sheets). The number of strands found in such domains may differ from one prote ...

composed of 8

β-strand The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

s that co-ordinates two or three

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

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.

Coupling with other domains

C2 domains are frequently found coupled to

enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...

domains; for example, the C2 domain in PTEN, brings the

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

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 Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins: : proteintyrosine phosphate + H2O = ...

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. In addition,

phosphatidylinositol 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

(PI3-kinase), an enzyme that

phosphorylates In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

phosphoinositides Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...

on the 3-

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

of the

inositol In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its elemental formula, formula is ...

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 and the prokaryote ''

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, bacillus (rod-shaped), anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present ...

'' where it is part of the alpha-toxin. 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.

Calcium and 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) (se
PDOC00379
and the protein kinase catalytic domain (se
PDOC00100
. Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding 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 Synaptotagmins (SYTs) constitute a family of cell membrane, membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 Protein isof ...

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.

3D structure

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 BAI1-associated protein 3 is a protein that in humans is encoded by the ''BAIAP3'' gene. BAIAP3 was identified as a protein-binding partner of BAI1. BAI1 is a p53-target gene that encodes a brain-specific angiogenesis inhibitor. The protein is a ...

; BCR; C2CD2; C2CD3;

CADPS Calcium-dependent secretion activator 1 is a protein that in humans is encoded by the ''CADPS'' gene. CADPS encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretor ...

; CADPS2; CAPN5;

CAPN6 Calpain-6 (also known as calpamodulin) is a protein in humans that is encoded by the ''CAPN6'' gene. Calpains are a ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. In the MEROPS protease enzyme classification system ...

; CC2D1A; CC2D1B; CPNE1; CPNE2; CPNE3; CPNE4; CPNE5; CPNE6; CPNE7;

CPNE8 Copine-8 is a protein that in humans is encoded by the ''CPNE8'' gene. Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene is one of several genes that encode a ...

; CPNE9; DAB2IP;

DOC2A Double C2-like domain-containing protein alpha is a protein that in humans is encoded by the ''DOC2A'' gene. There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2-like domai ...

; DOC2B; DYSF; ESYT1; ESYT3; FAM62A; FAM62B; FAM62C; FER1L3; FER1L5; HECW1; HECW2;

ITCH An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

;

ITSN1 Intersectin-1 is a protein that, in humans, is encoded by the ''ITSN1'' gene. Function The protein encoded by this gene is a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly ...

;

ITSN2 Intersectin-2 is a protein that in humans is encoded by the ''ITSN2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribe ...

; MCTP1; MCTP2; MTAC2D1;

NEDD4 E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the ''NEDD4'' gene. NEDD4 is an E3 ubiquitin ligase enzyme, tha ...

; NEDD4L; NEDL1; OTOF; PCLO; PIK3C2A; PIK3C2B; PIK3C2G;

PLA2G4A Cytosolic phospholipase A2 is an enzyme that in humans is encoded by the ''PLA2G4A'' gene. Function This gene encodes a member of the cytosolic phospholipase A2 group IV family. The enzyme catalyzes the hydrolysis of membrane phospholipids t ...

; PLA2G4B; PLA2G4D; PLA2G4E; PLA2G4F;

PLCB1 1-Phosphatidylinositol-4,5-bisphosphate phospholipase beta-1 is an enzyme that in humans is encoded by the ''PLCB1'' gene. Function The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol f ...

;

PLCB2 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-2 is an enzyme that in humans is encoded by the ''PLCB2'' gene. Function The gene codes for the enzyme phospholipase C β2. The enzyme catalyzes the formation of inositol 1,4,5-t ...

; PLCB3; PLCB4;

PLCD1 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-1 is an enzyme that in humans is encoded by the ''PLCD1'' gene. PLCd1 is essential to maintain homeostasis of the skin. See also Phospholipase C Phospholipase C (PLC) is a class o ...

; PLCD3;

PLCD4 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-4 is an enzyme that in humans is encoded by the ''PLCD4'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is ...

; PLCE1; PLCG1; PLCG2; PLCH1;

PLCH2 PLCH may stand for: * Plch, a municipality in the Czech Republic * The Public Library of Cincinnati and Hamilton County, a public library system in Cincinnati, Ohio, United States * Pulmonary Langerhans' cell histiocytosis, a type of interstitia ...

; PLCL1; PLCL2; PLCZ1; PRF1; PRKCA;

PRKCB1 Protein kinase C beta type is an enzyme that in humans is encoded by the ''PRKCB'' gene. Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and second messenger diacylglycerol. PK ...

;

PRKCE Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the ''PRKCE'' gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulat ...

;

PRKCG Protein kinase C gamma type is an enzyme that in humans is encoded by the ''PRKCG'' gene. Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and second messenger diacylglycerol. P ...

;

PRKCH Protein kinase C eta type is an enzyme that in humans is encoded by the ''PRKCH'' gene. Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium Calcium is a chemical element; it ...

;

RAB11FIP1 Rab11 family-interacting protein 1 (Rab11-FIP1) also known as Rab-coupling protein is a protein that in humans is encoded by the ''RAB11FIP1'' gene. Function Proteins of the large Rab GTPase family (see for example RAB1A) have regulatory rol ...

; RAB11FIP2; RAB11FIP5;

RASA1 RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120- kDa cytosolic human protein that provides two principal activities: * Inactivation of Ras from its active GTP-bound form to its inactive GDP-b ...

; RASA2; RASA3; RASA4; RASAL1; RASAL2; RGS3;

RIMS1 Regulating synaptic membrane exocytosis protein 1 is a protein that in humans is encoded by the ''RIMS1'' gene. Function RAB3A (MIM 179490), a member of the Ras superfamily of genes, is a synaptic vesicle protein that regulates synaptic vesicl ...

; RIMS2; RIMS3; RIMS4; RPGRIP1; RPGRIP1L; RPH3A; SGA72M; SMURF1; SMURF2; SYNGAP1; SYT1; SYT10; SYT11; SYT12; SYT13; SYT14; SYT14L; SYT15; SYT16; SYT17; SYT2; SYT3; SYT4;

SYT5 Synaptotagmin-5 is a protein that in humans is encoded by the ''SYT5'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcrib ...

; SYT6; SYT7; SYT8; SYT9; SYTL1; SYTL2; SYTL3;

SYTL4 Synaptotagmin-like protein 4 is a protein that in humans is encoded by the ''SYTL4'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA tha ...

; SYTL5; TOLLIP;

UNC13A Unc-13 homolog A (''C. elegans'') is a protein that in humans is encoded by the UNC13A gene. Function This gene encodes a member of the UNC13 family. UNC13A plays a role in vesicle maturation during exocytosis as a target of the diacylglycero ...

;

UNC13B Protein unc-13 homolog B is a protein that in humans is encoded by the ''UNC13B'' gene. Function This gene is expressed in the kidney cortical epithelial cells and is upregulated by hyperglycemia. The encoded protein shares a high level of sim ...

; UNC13C; UNC13D; WWC2;

WWP1 NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the ''WWP1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleoti ...

;

WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the ''WWP2'' gene. Function This gene encodes a member of the ...

; PTEN

References

External links

Phosphoinositide 3-kinase C2 family in Pfam
* - Orientations of C2 domains in membranes (OPM) {{Protein domains Peripheral membrane proteins Protein domains Protein superfamilies