| Calpain |
|
Crystal structure of the peptidase core of Calpain II.
|
| Identifiers |
| Symbol |
Calpain |
| Pfam |
PF00648 |
| Pfam clan |
CL0125 |
| InterPro |
IPR001300 |
| SMART |
CysPc |
| PROSITE |
PDOC50203 |
| MEROPS |
C2 |
| SCOP |
1mdw |
| SUPERFAMILY |
1mdw |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
| calpain-1 |
| Identifiers |
| EC number |
3.4.22.52 |
| CAS number |
689772-75-6 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
|
| calpain-2 |
| Identifiers |
| EC number |
3.4.22.53 |
| CAS number |
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 |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
|
A calpain (;[1] EC 3.4.22.52, EC 3.4.22.53) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.
Contents
- 1 Discovery
- 2 Cleavage specificity
- 3 Extended family
- 4 Function
- 5 Clinical significance
- 5.1 Pathology
- 5.2 Therapeutic inhibitors
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
Discovery
The history of calpain originates in 1964, when calcium-dependent proteolytic activities caused by a “calcium-activated neutral protease” (CANP) were detected in brain, lens of the eye and other tissues. In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle. These activities were caused by an intracellular cysteine protease not associated with the lysosome and having an optimum activity at neutral pH, which clearly distinguished it from the cathepsin family of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis on its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known,[2] it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signalling protein, calmodulin, and the cysteine protease of papaya, papain. Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed μ("mu")-calpain and m-calpain (a.k.a. calpain I and II), that differed primarily in their calcium requirements in vitro. Their names reflect the fact that they are activated by micro- and nearly millimolar concentrations of Ca2+ within the cell, respectively.[3]
To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric isoforms share an identical small (28k) subunit (CAPNS1 (formerly CAPN4)), but have distinct large (80k) subunits, known as calpain 1 and calpain 2 (each encoded by the CAPN1 and CAPN2 genes, respectively).
Cleavage specificity
No specific amino acid sequence is uniquely recognized by calpains. Amongst protein substrates, tertiary structure elements rather than primary amino acid sequences are likely responsible for directing cleavage to a specific substrate. Amongst peptide and small-molecule substrates, the most consistently reported specificity is for small, hydrophobic amino acids (e.g. leucine, valine and isoleucine) at the P2 position, and large hydrophobic amino acids (e.g. phenylalanine and tyrosine) at the P1 position.[4] Arguably, the best currently available fluorogenic calpain substrate is (EDANS)-Glu-Pro-Leu-Phe=Ala-Glu-Arg-Lys-(DABCYL), with cleavage occurring at the Phe=Ala bond.
Extended family
The Human Genome Project has revealed that there are more than a dozen other calpain isoforms, some with multiple splice variants.[5][6][7] As the first calpain whose three-dimensional structure was determined, m-calpain is the type-protease for the C2 (calpain) family in the MEROPS database.
| Gene |
Protein |
Aliases |
Tissue expression |
Disease linkage |
| CAPN1 |
Calpain 1 |
Calpain-1 large subunit, Calpain mu-type |
Central Nervous System |
|
| CAPN2 |
Calpain 2 |
Calpain-2 large subunit |
Central Nervous System |
|
| CAPN3 |
Calpain 3 |
|
skeletal muscle retina and lens specific |
Limb Girdle muscular dystrophy 2A |
| CAPN5 |
Calpain 5 |
|
ubiquitous (high in colon, small intestine and testis) |
might be linked to necrosis,
as it is an ortholog of the C. elegans necrosis gene tra-3 |
| CAPN6 |
Calpain 6 |
CAPNX, Calpamodulin |
|
|
| CAPN7 |
Calpain 7 |
palBH |
ubiquitous |
|
| CAPN8 |
Calpain 8 |
|
exclusive to stomach mucosa and the GI track |
might be linked to colon polyp formation |
| CAPN9 |
Calpain 9 |
|
exclusive to stomach mucosa and the GI track |
might be linked to colon polyp formation |
| CAPN10 |
Calpain 10 |
|
|
susceptibility gene for type II diabetes |
| CAPN11 |
Calpain 11 |
|
testis |
|
| CAPN12 |
Calpain 12 |
|
ubiquitous but high in hair follicle |
|
| CAPN13 |
Calpain 13 |
|
testis and lung |
|
| CAPN14 |
Calpain 14 |
|
ubiquitous |
|
| CAPN17 |
Calpain 17 |
|
Fish and amphibian-only |
|
| SOLH |
Calpain 15 |
Sol H (homolog of the drosophila gene sol) |
|
|
| CAPNS1 |
Calpain small subunit 1 |
Calpain 4 |
|
|
| CAPNS2 |
Calpain small subunit 2 |
|
|
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Function
Although the physiological role of calpains is still poorly understood, they have been shown to be active participants in processes such as cell mobility and cell cycle progression, as well as cell-type specific functions such as long-term potentiation in neurons and cell fusion in myoblasts. Under these physiological conditions, a transient and localized influx of calcium into the cell activates a small local population of calpains (for example, those close to Ca2+ channels), which then advance the signal transduction pathway by catalyzing the controlled proteolysis of its target proteins. Other reported roles of calpains are in cell function, helping to regulate clotting and the diameter of blood vessels, and playing a role in memory. Calpains have been implicated in apoptotic cell death, and appear to be an essential component of necrosis.
Enhanced calpain activity, regulated by CAPNS1, significantly contributes to platelet reactivity and thrombosis under hypoxic conditions.[8]
In the brain, while μ-calpain is mainly located in the cell body and dendrites of neurons and to a lesser extent in axons and glial cells, m-calpain is found in glia and a small amount in axons.[9] Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states.[10]
Clinical significance
Pathology
The structural and functional diversity of calpains in the cell is reflected in their involvement in the pathogenesis of a wide range of disorders. At least two well known genetic disorders and one form of cancer have been linked to tissue-specific calpains. When defective, the mammalian calpain 3 (also known as p94) is the gene product responsible for limb-girdle muscular dystrophy type 2A,[11][12] calpain 10 has been identified as a susceptibility gene for type II diabetes mellitus, and calpain 9 has been identified as a tumour suppressor for gastric cancer. Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer's disease,[13] and cataract formation, as well as secondary degeneration resulting from acute cellular stress following myocardial ischemia, cerebral (neuronal) ischemia, traumatic brain injury and spinal cord injury. Excessive amounts of calpain can be activated due to Ca2+ influx after cerebrovascular accident (during the ischemic cascade) or some types of traumatic brain injury such as diffuse axonal injury. Increase in concentration of calcium in the cell results in calpain activation, which leads to unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage. Excessively active calpain breaks down molecules in the cytoskeleton such as spectrin, microtubule subunits, microtubule-associated proteins, and neurofilaments.[14][15] It may also damage ion channels, other enzymes, cell adhesion molecules, and cell surface receptors.[9] This can lead to degradation of the cytoskeleton and plasma membrane. Calpain may also break down sodium channels that have been damaged due to axonal stretch injury,[16] leading to an influx of sodium into the cell. This, in turn, leads to the neuron's depolarization and the influx of more Ca2+. A significant consequence of calpain activation is the development of cardiac contractile dysfunction that follows ischemic insult to the heart. Upon reperfusion of the ischemic myocardium, there is development of calcium overload or excess in the heart cell (cardiomyocytes). This increase in calcium leads to activation of calpain.[17]
Therapeutic inhibitors
The exogenous regulation of calpain activity is therefore of interest for the development of therapeutics in a wide array of pathological states. As a few of the many examples supporting the therapeutic potential of calpain inhibition in ischemia, calpain inhibitor AK275 protected against focal ischemic brain damage in rats when administered after ischemia, and MDL28170 significantly reduced the size of damaged infarct tissue in a rat focal ischemia model. There are also known calpain inhibitors with neuroprotective effects: PD150606,[18] SJA6017,[19] ABT-705253,[20][21] and SNJ-1945.[22]
Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries.[23] However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.[23]
See also
References
- ^ http://dictionary.reference.com/browse/calpain?r=75&src=ref&ch=dic
- ^ Ohno S, Emori Y, Imajoh S, Kawasaki H, Kisaragi M, Suzuki K (1984). "Evolutionary origin of a calcium-dependent protease by fusion of genes for a thiol protease and a calcium-binding protein?". Nature 312 (5994): 566–70. doi:10.1038/312566a0. PMID 6095110.
- ^ Glass JD, Culver DG, Levey AI, Nash NR (April 2002). "Very early activation of m-calpain in peripheral nerve during Wallerian degeneration". J. Neurol. Sci. 196 (1-2): 9–20. doi:10.1016/S0022-510X(02)00013-8. PMID 11959150.
- ^ Cuerrier D, Moldoveanu T, Davies PL (December 2005). "Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions". J. Biol. Chem. 280 (49): 40632–41. doi:10.1074/jbc.M506870200. PMID 16216885.
- ^ Thompson V (2002-02-12). "Calpain Nomenclature". College of Agriculture and Life Sciences at the University of Arizona. Retrieved 2010-08-06.
- ^ Huang Y, Wang KK (August 2001). "The calpain family and human disease". Trends Mol Med 7 (8): 355–62. doi:10.1016/S1471-4914(01)02049-4. PMID 11516996.
- ^ Suzuki K, Hata S, Kawabata Y, Sorimachi H (February 2004). "Structure, activation, and biology of calpain". Diabetes. 53. Suppl 1: S12–8. doi:10.2337/diabetes.53.2007.s12. PMID 14749260.
- ^ "Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype.". Blood 123: 1250–60. Feb 2014. doi:10.1182/blood-2013-05-501924. PMID 24297866.
- ^ a b Lenzlinger PM, Saatman KE, Raghupathi R, Mcintosh TK (2000). "Chapter 1: Overview of basic mechanisms underlying neuropathological consequences of head trauma". In Newcomb JK, Miller LS, Hayes RL. Head trauma: basic, preclinical, and clinical directions. New York: Wiley-Liss. ISBN 0-471-36015-5.
- ^ Belcastro AN, Albisser TA, Littlejohn B (October 1996). "Role of calcium-activated neutral protease (calpain) with diet and exercise". Can J Appl Physiol 21 (5): 328–46. doi:10.1139/h96-029. PMID 8905185.
- ^ Richard I, Broux O, Allamand V et al. (April 1995). "Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A". Cell 81 (1): 27–40. doi:10.1016/0092-8674(95)90368-2. PMID 7720071.
- ^ Ono Y, Shimada H, Sorimachi H et al. (July 1998). "Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A". J. Biol. Chem. 273 (27): 17073–8. doi:10.1074/jbc.273.27.17073. PMID 9642272.
- ^ Yamashima T (2013). "Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'--a perspective review". PROGRESS IN NEUROLOGY 105: 1–23. doi:10.1016/j.pneurobio.2013.02.004. PMID 23499711.
- ^ Liu J, Liu MC, Wang KK (April 2008). "Calpain in the CNS: from synaptic function to neurotoxicity". Sci Signal. 1 (14): re 1. doi:10.1126/stke.114re1. PMID 18398107.
- ^ Castillo MR, Babson JR (October 1998). "Ca2+-dependent mechanisms of cell injury in cultured cortical neurons". Neuroscience 86 (4): 1133–44. doi:10.1016/S0306-4522(98)00070-0. PMID 9697120.
- ^ Iwata A, Stys PK, Wolf JA et al. (May 2004). "Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors". J. Neurosci. 24 (19): 4605–13. doi:10.1523/JNEUROSCI.0515-03.2004. PMID 15140932.
- ^ Wang KK, Larner SF, Robinson G, Hayes RL (December 2006). "Neuroprotection targets after traumatic brain injury". Curr. Opin. Neurol. 19 (6): 514–9. doi:10.1097/WCO.0b013e3280102b10. PMID 17102687.
- ^ Wang KK, Nath R, Posner A, Raser KJ, Buroker-Kilgore M, Hajimohammadreza I, Probert A W, Marcoux FW, Ye Q, Takano E, Hatanaka M, Maki M, Caner H, Collins JL, Fergus A, Lee KS, Lunney EA, Hays SJ, Yuen P (June 1996). "An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective". Proc. Natl. Acad. Sci. U.S.A. 93 (13): 6687–92. doi:10.1073/pnas.93.13.6687. PMC 39087. PMID 8692879.
- ^ Kupina NC, Nath R, Bernath EE, Inoue J, Mitsuyoshi A, Yuen PW, Wang KK, Hall ED (November 2001). "The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury". J. Neurotrauma 18 (11): 1229–40. doi:10.1089/089771501317095269. PMID 11721741.
- ^ Lubisch W, Beckenbach E, Bopp S, Hofmann HP, Kartal A, Kästel C, Lindner T, Metz-Garrecht M, Reeb J, Regner F, Vierling M, Möller A (June 2003). "Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: discovery of potent water-soluble calpain inhibitors with oral bioavailability". J. Med. Chem. 46 (12): 2404–12. doi:10.1021/jm0210717. PMID 12773044.
- ^ Nimmrich V, Reymann KG, Strassburger M, Schöder UH, Gross G, Hahn A, Schoemaker H, Wicke K, Möller A (April 2010). "Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures". Br. J. Pharmacol. 159 (7): 1523–31. doi:10.1111/j.1476-5381.2010.00652.x. PMC 2850408. PMID 20233208.
- ^ Koumura A, Nonaka Y, Hyakkoku K, Oka T, Shimazawa M, Hozumi I, Inuzuka T, Hara H (November 2008). "A novel calpain inhibitor, ((1S)-1((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl) carbamic acid 5-methoxy-3-oxapentyl ester, protects neuronal cells from cerebral ischemia-induced damage in mice". Neuroscience 157 (2): 309–18. doi:10.1016/j.neuroscience.2008.09.007. PMID 18835333.
- ^ a b White V (1999-10-21). "– ‘Biochemical Storm’ Following Brain Trauma An Important Factor In Treatment, University of Florida Researcher Finds". University of Florida News. Retrieved 2010-08-07.
Further reading
- Liu J, Liu MC, Wang KK (2008). "Calpain in the CNS: from synaptic function to neurotoxicity". Sci Signal 1 (14): re1. doi:10.1126/stke.114re1. PMID 18398107.
- Suzuki K, Hata S, Kawabata Y, Sorimachi H (February 2004). "Structure, activation, and biology of calpain". Diabetes. 53. Suppl 1: S12–8. doi:10.2337/diabetes.53.2007.s12. PMID 14749260.
- Yuen P-W, Wang KW (1999). Calpains : Pharmacology and Toxicology of a Cellular Protease. Boca Raton: CRC Press. ISBN 1-56032-713-8.
External links
- Calpain at the US National Library of Medicine Medical Subject Headings (MeSH)
- CaMPDB, Calpain for Modulatory Proteolysis Database
- The Calpain Family of Proteases. (2001). University of Arizona.
- Calpain Info with links in the Cell Migration Gateway
- Alzheimers and calpain protease, PMAP The Proteolysis Map-animation.
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Proteases: cysteine proteases (EC 3.4.22)
|
|
| Caspase |
- Caspase 1
- Caspase 2
- Caspase 3
- Caspase 4
- Caspase 5
- Caspase 6
- Caspase 7
- Caspase 8
- Caspase 9
- Caspase 10
- Caspase 12
- Caspase 13
- Caspase 14
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|
| Fruit-derived |
- Papain
- Ficain
- Bromelain
- Actinidain
|
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| Calpain |
- CAPN1
- CAPN2
- CAPN3
- CAPN5
- CAPN6
- CAPN7
- CAPN8
- CAPN9
- CAPN10
- CAPN11
- CAPN12
- CAPN13
- CAPN14
- CAPNS1
- CAPNS2
|
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| Cathepsin |
|
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| Other |
- Clostripain
- Cancer procoagulant
- Separase
- Autophagin
- Cruzipain
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|
- Biochemistry overview
- Enzymes overview
- By EC number: 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Cell signaling: calcium signaling and calcium metabolism
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| Cell membrane |
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Ion pumps
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- SERCA
- Sodium-calcium exchanger
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Cell membrane calcium channels
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- VDCC
- TRP
- NMDA receptor
- AMPA receptor
- 5-HT3 receptor
- P2X purinoreceptor
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Adhesion molecules
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Other
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Intracellular signaling
& calc. regulation |
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Second messengers
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Store gates
(ligand-gated calcium channel)
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Molecular switches, and kinases
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- Troponin C
- Calmodulin
- CaM kinases
- PKC
- NCS
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Chelators and calcium sensors
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- Calbindin
- S100
- pervalbumin
- Calretinin
- Calsequestrin
- Sarcalumenin
- Phospholamban
- Synaptotagmins
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Proteases
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Cytoskeleton remodeling proteins
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Chaperones
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Other
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Calcium-binding
protein domains |
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| Extracellular ligands |
- Parathyroid hormone
- Calcitonin
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| Calcium-binding proteins |
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Intracellular calcium-sensing proteins
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- Calmodulin
- Calnexin
- Calreticulin
- Gelsolin
- neuronal
- Hippocalcin
- Neurocalcin
- Recoverin
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Membrane protein
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- Vitamin D-dependent calcium-binding protein/Calbindin
- Calexcitin
- Calsequestrin
- Osteocalcin
- Osteonectin
- S-100
- Synaptotagmin
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Cytoskeleton
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Extracellular matrix
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Index of signal transduction
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| Description |
- Intercellular
- neuropeptides
- growth factors
- cytokines
- hormones
- Cell surface receptors
- ligand-gated
- enzyme-linked
- G protein-coupled
- immunoglobulin superfamily
- integrins
- neuropeptide
- growth factor
- cytokine
- Intracellular
- adaptor proteins
- GTP-binding
- MAP kinase
- Calcium signaling
- Lipid signaling
- Pathways
- hedgehog
- Wnt
- TGF beta
- MAPK ERK
- notch
- JAK-STAT
- apoptosis
- hippo
- TLR
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