Family C2

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

C2A

Summary Holotypes Alignment Tree Genomes Literature

Summary for family C2

NamePeptidase family C2 (calpain family)
Family type peptidaseC02.002 - calpain-2 (Homo sapiens), MEROPS Accession MER0000964 (peptidase unit: 75-327)
Content of familyPeptidase family C2 contains endopeptidases termed "calpains".
History Identifier created: Biochem.J. 290:205-218 (1993)
During the mid-1960s calcium-dependent proteolytic activities were detected in brain, lens and other tissues, and in the late 1970s the enzymes were isolated and characterised (e.g. Mellgren, 1980). The early name 'calcium-dependent neutral protease' has now been replaced by 'calpain'.
Catalytic typeCysteine
Active siteThe peptidase units of the calpains show a distant similarity in structure to that of papain (family C1) and, catalysis depends upon a catalytic dyad of Cys and His, as in other peptidases in clan CA.
Activities and specificitiesCalpain 1 (C02.001) and calpain 2 (C02.002) are the enzymes best known in regard to peptidase activity. They are endopeptidases dependent on neutral pH, reducing conditions and calcium ions. Calpain 1 and calpain 2 are also known as micro-calpain and milli-calpain respectively because they require micromolar and millimolar concentrations of calcium for maximal activity. The rules governing specificity are not obvious, but hydrophobic residues (Tyr, Met, Leu, Val) and also Arg tend to be found in the P2 position.
InhibitorsLow molecular mass inhibitors of calpains include general thiol-blocking agents and also compound E-64 (Parkes et al., 1985), as well as leupeptin (Toyo-Oka et al., 1978) and other peptide aldehydes. Natural inhibitors include calpastatin (LI27-001) and the cystatin-like inhibitor unit 2 of kininogen (I25.016).
Molecular structureThe molecules of calpains 1 and 2 are heterodimers in which the large subunits contain the peptidase units, and the small subunit is common to both enzymes. Calcium-binding domains occur in both large and small subunits. Some other calpains have very different domain structures (Sorimachi, 2004). The polypeptides do not have signal peptides, and the calpains are predominantly cytosolic proteins.
ClanCA
Basis of clan assignmentProtein fold of the peptidase unit for members of this family resembles that of papain, the type example for clan CA.
Distribution of family Bacteria details  
Archaea -  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsHow calpain activity is regulated in cells is still unclear, but the calpains seem to participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, signal transduction pathways and apoptosis. The Drosophila variant of calpain 10 (C02.010) is known as 'small optic lobes' because of its role in development of the brain (Delaney et al., 1991).
Pharmaceutical and biotech relevanceActivity of calpains resulting from loss of calcium homeostasis is thought to contribute to morbidity associated with myocardial infarction and stroke (Goll et al., 2003). Mutations in the gene for calpain 3 (C02.004) are responsible for limb-girdle muscular dystrophy type 2A (Fanin et al., 2003). Variations in the calpain 10 gene (C02.018) may be connected in some way to type 3 diabetes (Weedon et al., 2003).
Statistics for family C2Sequences:6516
Identifiers:38
Identifiers with PDB entries:6
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily C2A
Name Peptidase subfamily C2A
Subfamily type peptidase C02.002 - calpain-2 (Homo sapiens), MEROPS Accession MER0000964 (peptidase unit: 75-327)
Active site residues Q99 C105 H262 N286 
Statistics Sequences: 6504
Identifiers: 38
Identifiers with PDB entries: 6
Other databases CATH 1.10.238.10
HOMSTRAD Peptidase_C2
HSSP 1kfx
INTERPRO IPR001300
PANTHER PTHR10183
PFAM PF00648
SCOP 54040
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
calpain-1C02.001Yes
calpain-2C02.002Yes
calpain CC02.003-
calpain-3C02.004Yes
calpain-9C02.006Yes
calpain-8C02.007-
Rim13 peptidaseC02.008-
calpain tra-3C02.009-
calpain-15C02.010-
calpain-5C02.011-
calpain-11C02.013-
calpain AC02.014-
calpain BC02.015-
calpain-12C02.017-
calpain-10C02.018-
phytocalpainC02.019-
calpain-13C02.020Yes
calpain-14C02.021-
Tpr peptidase (Porphyromonas gingivalis)C02.022-
calpain (Schistosoma sp.)C02.023-
calpain B (Gecarcinus-type})C02.024-
calpain M (Gecarcinus-type)C02.025-
Mername-AA248C02.026-
Mername-AA252 peptidaseC02.027-
calpain-7C02.028-
calpain (Plasmodium-type)C02.029Yes
RIM13 peptidase (Saccharomyces cerevisiae)C02.030-
calpamodulinC02.971-
androglobinC02.972-
W05G11.4 g.p. (Caenorhabditis elegans)C02.A01-
T11A5.6 g.p. (Caenorhabditis elegans)C02.A02-
clp-1 g.p. (Caenorhabditis elegans)C02.A03-
clp-6 g.p. (Caenorhabditis elegans)C02.A04-
clp-7 g.p. (Caenorhabditis elegans)C02.A05-
clp-4 g.p. (Caenorhabditis elegans)C02.A06-
F44F1.1 g.p. (Caenorhabditis elegans)C02.A07-
F44F1.3 g.p. (Caenorhabditis elegans)C02.A08-
clec-119 g.p. (Caenorhabditis elegans)C02.A09-
subfamily C2A non-peptidase homologuesnon-peptidase homologue-
subfamily C2A unassigned peptidasesunassigned-