Calpains (EC number|18.104.22.168, EC number|22.214.171.124) are a 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 (former CAPN4, a.k.a. 30K)), and the endogenous calpain-specific inhibitor, calpastatin.
The history of calpain originates during the mid-1960s, when calcium-dependent proteolytic activities caused by a “calcium-activated neutral protease” (CANP) were detected in
brain, lens of the eyeand 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 lysosomeand having an optimum activity at neutral pH, which clearly distinguished it from the cathepsinfamily of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysison its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known,Ohno S, Emori Y, Imajoh S, Kawasaki H, Kisaragi M, Suzuki K. (1984). [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6095110 Evolutionary origin of a calcium-dependent protease by fusion of genes for a thiol protease and a calcium-binding protein?] "Nature". 312: 566-570.] it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signaling 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 millimolar concentrations of Ca2+ within the cell, respectively.Glass JD, Culver DG, Levey AI, and Nash NR. (2002). [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11959150&dopt=Citation Very early activation of m-calpain in peripheral nerve during Wallerian degeneration.] "Journal of the Neurological Sciences". 196(1-2): 9-20.] To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric isoforms share an identical small (30k) subunit (CAPNS1 (former CAPN4)), but have distinct large (80k) subunits.
Recently, sequencing of the human genome has revealed
genes for more than a dozen other calpain isoforms, some with multiple splice variants. As the first calpain whose almost complete three-dimensional structure was determined, m-calpain is the type-protease for the C2 (calpain) family in the MEROPS database.
Although the physiological roles of calpains are still poorly understood, they have been shown to be active participants in processes such as
cell mobilityand cell cycleprogression, as well as cell-type specific functions such as long-term potentiationin neurons and cell fusionin 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 clottingand 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.
In the brain, while μ-calpain is mainly located in the
cell bodyand 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. Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states.Belcastro AN, Albisser TA, Littlejohn B (1996). [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8905185&dopt=Citation Role of calcium-activated neutral protease (calpain) with diet and exercise.] "Canadian Journal of Applied Physiology". 21(5):328-346. PMID 8905185. Retrieved January 19, 2007.]
Calpains in pathologies
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,Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C, Beckmann JS. (1995). [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=7720071 Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.] "Cell". 81:27-40.] Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K. (1998). [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9642272 Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A.] "J. Biol. Chem.". 273:17073-17078.] calpain 10 has been identified as a susceptibility gene for type II diabetes mellitus, and calpain 9 has been identified as a tumor 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, 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 injurysuch 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 cytoskeletonsuch as spectrin, microtubulesubunits, microtubule-associated proteins, and neurofilaments. Castillo MR and Babson JR. (1998). [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9697120&dopt=Abstract Ca2+-dependent mechanisms of cell injury in cultured cortical neurons.] "Neuroscience". 86(4): 1133-1144. PMID 9697120 Retrieved on January 19, 2007.] It may also damage ion channels, other enzymes, cell adhesion molecules, and cell surface receptors.Lenzlinger PM, Saatman KE, Raghupathi R, Mcintosh TK. 2001. Overview of basic mechanisms underlying neuropathological consequences of head trauma. Chapter 1. In, "Head trauma: Basic, preclinical, and clinical directions". Miller LP and Hayes RL, eds. Wiley Liss, (a John Wiley and Sons publication) New York. ] 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,Iwata A, Stys PK, Wolf JA, Chen XH, Taylor AG, Meaney DF, and Smith DH. (2004). [http://www.jneurosci.org/cgi/content/full/24/19/4605 Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors.] "The Journal of Neuroscience". 24(19): 4605-4613. PMID 15140932 Retrieved on January 19, 2007.] leading to an influx of sodiuminto the cell. This, in turn, leads to the neuron's depolarizationand the influx of more Ca2+. A significant consequence of calpain activation is the development of cardiac contractile dysfunctionthat 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. 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 AK275protected against focal ischemic brain damage in rats when administered after ischemia, and MDL28170significantly reduced the size of damaged infarct tissue in a rat focal ischemia model.
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.White V. (1999). [http://www.napa.ufl.edu/99news/braintra.htm 'Biochemical Storm' Following Brain Trauma an Important Factor in Treatment, University of Florida Researcher Finds.] Retrieved on
January 19, 2007.] However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.
Calpain 1 and 2 are heterodimeric enzymes that share a common 28k regulatory subunit (encoded by the "CAPNS1" (former "CAPN4") gene).
amino acidsequence is uniquely recognized by calpains. Amongst protein substrates, tertiary structureelements rather than primary amino acid sequences are likely responsible for directing cleavage to a specific substrate. Amongst peptideand small-molecule substrates, the most consistently reported specificity is for small, hydrophobicamino acids (e.g. leucine, valineand isoleucine) at the P2 position, and large hydrophobic amino acids (e.g. phenylalanineand tyrosine) at the P1 position.Cuerrier D, et al (2005). [http://www.jbc.org/cgi/content/full/280/49/40632 Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions.] "Journal of Biological Chemistry". 280(49):40632-40641. PMID 16216885 Retrieved on January 19, 2007. ] Arguably, the best currently available fluorogeniccalpain substrate is ( EDANS)-Glu-Pro-Leu-Phe=Ala-Glu-Arg-Lys-( DABCYL), with cleavage occurring at the Phe=Ala bond.
* [http://www.tlc-aaea.org/calpains/index.html The Calpain Family of Proteases.] (2001). University of Arizona.
* Wang, K.K.W. and Yuen, P.-w. (Eds.) (1999) [http://www.amazon.com/dp/1560327138/ Calpain: The Pharmacology and Toxicology of Calcium-Dependent Protease.] Taylor and Francis, PA; 22 Chapters, 441 pages.
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