Calpain-2 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
EC no. | 3.4.22.53 | ||||||||
CAS no. | 702693-80-9 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Calpain-2 ( EC 3.4.22.53, calcium-activated neutral protease II, m-calpain, milli-calpain) is an intracellular heterodimeric calcium-activated cysteine protease. [1] [2] This enzyme catalyses the following chemical reaction
This enzyme belongs to the peptidase family C2. It is one of 15 proteins in the calpain family. [3]
Calpain-2 is a heterodimer of a catalytic subunit encoded by CAPN2 gene and a regulatory subunit CAPNS1. [1] [4] [5] The catalytic subunit consists of four domains: protease core 1 domain (PC1), protease core 2 domain (PC2), calpain-type beta-sandwich-like domain (CBSW), and penta EF-hand domain (PEF(L)). [3] The catalytic cleft is formed by PC1 and PC2 upon calcium binding. [6] The catalytic triad consists of residues C105, H262, and N286. Noteworthy, CAPN2 also contains an N-terminal anchor helix, which however is cleaved off upon protease activation. [7] It is believed to play a role in a regulation of catalytic activity.
The regulatory subunit consists of two domains: a glycine-rich domain (GR), and penta EF-hand domain (PEF(S)). [3] The interaction of PEF(S) and PEF(L) through an unpaired EF-hand motif causes dimerization of the two subunits. Calpain-2 heterodimer is highly homologous to calpain-1, which is formed by a catalytic CAPN1 and a regulatory CAPNS1 subunits. [3]
There is no known consensus sequence for calpain-2 proteolysis, but there is evidence for over 130 potential substrates. [8] Proteolytic cleavage by calpain-2 is regulated by presence of Ca2+ ions. It requires supraphysiological (low millimolar) concentration of Ca2+ for activation. [6] Intracellular concentration of Ca2+ (approx. 100 nM) [9] is insufficient for activating calpain-2, so activation occurs upon influx of ions from extracellular space or from endoplasmic reticulum. In addition, calpain-1/2 can be inhibited by calpastatin (encoded by the CAST gene) which binds to the PEF domains of the catalytic and regulatory subunits of calpains-1/2. It prohibits substrate binding to the active site through steric hindrance. [10]
Upregulation of calpain-2 is linked to increased aggressiveness of cancer. [11] [12] There is evidence suggesting that the mechanism of action is through cleavage of substrates involved in cell migration, invasion, and sensitivity to chemotherapeutic agents. [13] [14] [15]
Previously used nomenclature used Roman numerals to denote calpain-2 domains starting from the N-terminus of CAPN2 and ending at C-terminus of CAPNS1. For example, PEF(L) and PEF(S) were referred to as Domain IV and Domain VI, respectively. [16]
Calpain-2 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
EC no. | 3.4.22.53 | ||||||||
CAS no. | 702693-80-9 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
|
Calpain-2 ( EC 3.4.22.53, calcium-activated neutral protease II, m-calpain, milli-calpain) is an intracellular heterodimeric calcium-activated cysteine protease. [1] [2] This enzyme catalyses the following chemical reaction
This enzyme belongs to the peptidase family C2. It is one of 15 proteins in the calpain family. [3]
Calpain-2 is a heterodimer of a catalytic subunit encoded by CAPN2 gene and a regulatory subunit CAPNS1. [1] [4] [5] The catalytic subunit consists of four domains: protease core 1 domain (PC1), protease core 2 domain (PC2), calpain-type beta-sandwich-like domain (CBSW), and penta EF-hand domain (PEF(L)). [3] The catalytic cleft is formed by PC1 and PC2 upon calcium binding. [6] The catalytic triad consists of residues C105, H262, and N286. Noteworthy, CAPN2 also contains an N-terminal anchor helix, which however is cleaved off upon protease activation. [7] It is believed to play a role in a regulation of catalytic activity.
The regulatory subunit consists of two domains: a glycine-rich domain (GR), and penta EF-hand domain (PEF(S)). [3] The interaction of PEF(S) and PEF(L) through an unpaired EF-hand motif causes dimerization of the two subunits. Calpain-2 heterodimer is highly homologous to calpain-1, which is formed by a catalytic CAPN1 and a regulatory CAPNS1 subunits. [3]
There is no known consensus sequence for calpain-2 proteolysis, but there is evidence for over 130 potential substrates. [8] Proteolytic cleavage by calpain-2 is regulated by presence of Ca2+ ions. It requires supraphysiological (low millimolar) concentration of Ca2+ for activation. [6] Intracellular concentration of Ca2+ (approx. 100 nM) [9] is insufficient for activating calpain-2, so activation occurs upon influx of ions from extracellular space or from endoplasmic reticulum. In addition, calpain-1/2 can be inhibited by calpastatin (encoded by the CAST gene) which binds to the PEF domains of the catalytic and regulatory subunits of calpains-1/2. It prohibits substrate binding to the active site through steric hindrance. [10]
Upregulation of calpain-2 is linked to increased aggressiveness of cancer. [11] [12] There is evidence suggesting that the mechanism of action is through cleavage of substrates involved in cell migration, invasion, and sensitivity to chemotherapeutic agents. [13] [14] [15]
Previously used nomenclature used Roman numerals to denote calpain-2 domains starting from the N-terminus of CAPN2 and ending at C-terminus of CAPNS1. For example, PEF(L) and PEF(S) were referred to as Domain IV and Domain VI, respectively. [16]