A C2 domain is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
structural domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
involved in targeting proteins to
cell membranes. The typical version (PKC-C2) has a
beta-sandwich
Beta-sandwich, 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 protein ...
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 g ...
s that co-ordinates two or three
calcium
Calcium is a chemical element with the 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 ...
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
Enzymes () are proteins that act as biological catalysts 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 products. ...
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 chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
phosphoinositides
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
on the 3-hydroxyl group of the
inositol
Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors and ...
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, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present in nature an ...
'' 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 Ca
2+-dependent manner, some C2 domains can interact with the membrane without binding to Ca
2+. Similarly, C2 domains have been evolved to have different specificities for lipids. Many C2 domains such as
synaptotagmin
Synaptotagmins (SYTs) constitute a family of 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 isoforms in the mammalian s ...
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 Ca
2+ 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 Ca
2+-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
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 secreto ...
;
CADPS2
Calcium-dependent secretion activator 2 is a protein that in humans is encoded by the ''CADPS2'' gene.
Function
This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium-binding proteins ...
;
CAPN5;
CAPN6;
CC2D1A;
CC2D1B;
CPNE1;
CPNE2;
CPNE3;
CPNE4
Copine-4 is a protein that in humans is encoded by the ''CPNE4'' gene.
Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm
In cell biology, the cytoplasm is all of th ...
;
CPNE5;
CPNE6;
CPNE7
Copine 7 is a protein that in humans is encoded by the CPNE7 gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gen ...
;
CPNE8;
CPNE9;
DAB2IP
Disabled homolog 2-interacting protein is a protein that in humans is encoded by the ''DAB2IP'' gene.
DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor gene and is inactivated by methylation in prostate ...
;
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
Double C2-like domain-containing protein beta is a protein that in humans is encoded by the ''DOC2B'' gene.
Function
There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2 ...
;
DYSF;
ESYT1;
ESYT3;
FAM62A
Extended synaptotagmin-1 is a protein in humans that is encoded by the ''ESYT1'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...
;
FAM62B;
FAM62C;
FER1L3;
FER1L5;
HECW1;
HECW2;
ITCH
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
;
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.
This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersecti ...
;
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, that ...
;
NEDD4L
Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme (ubiquitin ligase) of the NEDD4 family.
In human the protein is encoded by the ''NEDD4L'' gene. In mouse the protein is commonly known as NE ...
;
NEDL1;
OTOF
Otoferlin is a protein that in humans is encoded by the ''OTOF'' gene.
Function
Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has three C2 domains, a single ca ...
;
PCLO
Protein piccolo is a protein that in humans is encoded by the ''PCLO'' gene.
Function
Synaptic vesicles dock and fuse in the active zone of the plasma membrane at chemical synapses. The presynaptic cytoskeletal matrix (PCM), which is associated ...
;
PIK3C2A
Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the ''PIK3C2A'' gene.
The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases p ...
;
PIK3C2B;
PIK3C2G
Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing gamma polypeptide is an enzyme that in humans is encoded by the ''PIK3C2G'' gene.
The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases ...
;
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 to r ...
;
PLA2G4B
Phospholipase A2, group IVB (cytosolic), also known as PLA2G4B, is a human gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birt ...
;
PLA2G4D
PLA may refer to:
Organizations Politics and military
* People's Liberation Army, the armed forces of China and of the ruling Chinese Communist Party
* People's Liberation Army (disambiguation)
** Irish National Liberation Army, formerly called ...
;
PLA2G4E
PLA may refer to:
Organizations Politics and military
* People's Liberation Army, the armed forces of China and of the ruling Chinese Communist Party
* People's Liberation Army (disambiguation)
** Irish National Liberation Army, formerly called ...
;
PLA2G4F
PLA may refer to:
Organizations Politics and military
* People's Liberation Army, the armed forces of China and of the ruling Chinese Communist Party
* People's Liberation Army (disambiguation)
** Irish National Liberation Army, formerly called ...
;
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 fro ...
;
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-tris ...
;
PLCB3
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-3 is an enzyme that in humans is encoded by the ''PLCB3'' gene.
The gene codes for the enzyme phospholipase C β3. The enzyme catalyzes the formation of inositol 1,4,5-trisphosphate an ...
;
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 of ...
;
PLCD3
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-3 is an enzyme that in humans is encoded by the ''PLCD3'' gene.
Function
This gene encodes a member of the phospholipase C family, which catalyze the hydrolysis of phosphatidylin ...
;
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 (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units o ...
;
PLCE1
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) is an enzyme that in humans is encoded by the ''PLCE1'' gene. This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bi ...
;
PLCG1
Phospholipase C, gamma 1, also known as PLCG1,is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the ''PLCG1'' gene and is part of the PLC superfamily.
Function
PLCγ1 is a cell grow ...
;
PLCG2
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the ''PLCG2'' gene.
Function
Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols an ...
;
PLCH1;
PLCH2 PLCH may stand for:
* Plch, a municipality in the Czech Republic
* The Public Library of Cincinnati and Hamilton County
Cincinnati and Hamilton County Public Library (CHPL) is a public library system in the United States. In addition t ...
;
PLCL1;
PLCL2 PLCL may refer to:
* Park Lane College Leeds, a former British further education college, now part of Leeds City College
* ''Parker Lewis Can't Lose
''Parker Lewis Can't Lose'' is an American teen sitcom that originally aired on Fox from Sept ...
;
PLCZ1;
PRF1;
PRKCA
Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the ''PRKCA'' gene.
Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messe ...
;
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 diacylglycero ...
;
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 regulate ...
;
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 and the second messenger diacylglycerol. ...
;
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 role ...
;
RAB11FIP2
Rab11 family-interacting protein 2 is a protein that in humans is encoded by the ''RAB11FIP2'' gene.
Interactions
RAB11FIP2 has been shown to interact with MYO5B, RAB11A
Ras-related protein Rab-11A is a protein that in humans is encoded by the ' ...
;
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 (protein), Ras from its active Guanosine triphosphate, G ...
;
RASA2;
RASA3
Ras GTPase-activating protein 3 is an enzyme that in humans is encoded by the ''RASA3'' gene.
The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RA ...
;
RASA4;
RASAL1;
RASAL2;
RGS3
Regulator of G-protein signaling 3 is a protein that in humans is encoded by the ''RGS3'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''genera ...
;
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
Regulating synaptic membrane exocytosis protein 2 is a protein that in humans is encoded by the ''RIMS2'' gene.
Interactions
RIMS2 has been shown to interact with YWHAH, RAPGEF4, and UNC13A
Unc-13 homolog A (''C. elegans'') is a protein tha ...
;
RIMS3;
RIMS4;
RPGRIP1
X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 is a protein in the ciliary transition zone that in humans is encoded by the ''RPGRIP1'' gene. RPGRIP1 is a multi-domain protein containing a coiled-coil domain at the N-term ...
;
RPGRIP1L
RPGRIP1L is a human gene.
Function
The protein encoded by this gene is localized to primary cilia and centrosomes in ciliated human epithelial kidney cells and retinal pigment epithelial cells . RPGRIP1L colocalized at the basal body-centrosome ...
;
RPH3A
Rabphilin-3A is a protein that in humans is encoded by the ''RPH3A'' gene.
It contains two C2 domains and binds calcium ions at low micromolar concentration. Rabphilin was shown to regulate neurotransmitter release in hippocampal neurons after neu ...
;
SGA72M;
SMURF1
E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the ''SMURF1'' gene.
Function
This gene encodes a ubiquitin ligase that is specific for receptor-regulated SMAD proteins in the bone morphogenetic protein ( BMP) pat ...
;
SMURF2
E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the ''SMURF2'' gene which is located at chromosome 17q23.3-q24.1.
Interactions
SMURF2 has been shown to interact with:
* Mothers against decapentaplegic homolog 1,
* ...
;
SYNGAP1
Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the ''SYNGAP1'' gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition a ...
;
SYT1
Synaptotagmin-1 is a protein that in humans is encoded by the ''SYT1'' gene.
Function
Synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as sensors for calcium ions (Ca2+) in the process of vesicular trafficking ...
;
SYT10;
SYT11;
SYT12;
SYT13;
SYT14;
SYT14L;
SYT15;
SYT16;
SYT17;
SYT2;
SYT3;
SYT4;
SYT5;
SYT6;
SYT7;
SYT8;
SYT9
Synaptotagmin-9 is a protein that in humans is encoded by the ''SYT9'' gene.
Interactions
SYT9 has been shown to interact with SYNCRIP, TUBB and TRPV1
The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as ...
;
SYTL1;
SYTL2;
SYTL3;
SYTL4;
SYTL5;
TOLLIP
Toll interacting protein, also known as TOLLIP, is an inhibitory adaptor protein that in humans is encoded by the ''TOLLIP'' gene.
Function and regulation
It is an inhibitory adaptor protein within Toll-like receptors (TLR). The TLR pathway is ...
;
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
Protein unc-13 homolog D, also known as munc13-4, is a protein that in humans is encoded by the ''UNC13D'' gene.
Function
Munc13-4 is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-te ...
;
WWC2;
WWP1
NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the ''WWP1'' gene.
Function
WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellul ...
;
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