Calpain-2

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Calpain-2
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EC no. 3.4.22.53
CAS no. 702693-80-9
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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

Contents

Broad endopeptidase specificity

This enzyme belongs to the peptidase family C2. It is one of 15 proteins in the calpain family. [3]

Structure

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]

Properties

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]

Calpain-2 in Cancer

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]

Domain Nomenclature

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]

See also

Related Research Articles

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Calcineurin</span> Class of enzymes

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+-Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

<span class="mw-page-title-main">Death effector domain</span> InterPro Domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).

<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases 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.

Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. In humans they are divided into three subtypes: large conductance or BK channels, which have very high conductance which range from 100 to 300 pS, intermediate conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and small conductance or SK channels with small conductances from 2-25 pS.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

<span class="mw-page-title-main">Phosphorylase kinase</span>

Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase “a” form over the less active glycogen phosphorylase b.

<span class="mw-page-title-main">L-type calcium channel</span> Family of transport proteins

The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

Calpain-1 is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">CAPN10</span> Protein-coding gene in the species Homo sapiens

Calpain-10 is a protein that in humans is encoded by the CAPN10 gene.

<span class="mw-page-title-main">Calpain-2 catalytic subunit</span> Protein-coding gene in the species Homo sapiens

Calpain-2 catalytic subunit is a protein that in humans is encoded by the CAPN2 gene.

<span class="mw-page-title-main">Calpain-1 catalytic subunit</span> Protein-coding gene in the species Homo sapiens

Calpain-1 catalytic subunit(CANP 1) is a protein that in humans is encoded by the CAPN1 gene.

<span class="mw-page-title-main">Calcium-activated potassium channel subunit alpha-1</span> Voltage-gated potassium channel protein

Calcium-activated potassium channel subunit alpha-1 also known as large conductance calcium-activated potassium channel, subfamily M, alpha member 1 (KCa1.1), or BK channel alpha subunit, is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.

<span class="mw-page-title-main">CDK5R1</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the CDK5R1 gene.

<span class="mw-page-title-main">Calpastatin</span> Protein-coding gene in the species Homo sapiens

Calpastatin is a protein that in humans is encoded by the CAST gene.

Calpain small subunit 1(CSS1), is a protein that in humans is encoded by the CAPNS1 gene.

Ca<sub>v</sub>1.3 Protein-coding gene in the species Homo sapiens

Calcium channel, voltage-dependent, L type, alpha 1D subunit is a protein that in humans is encoded by the CACNA1D gene. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

<span class="mw-page-title-main">Calpain-9</span> Protein-coding gene in the species Homo sapiens

Calpain-9 is a protein that in humans is encoded by the CAPN9 gene.

References

  1. 1 2 Strobl S, Fernandez-Catalan C, Braun M, Huber R, Masumoto H, Nakagawa K, et al. (January 2000). "The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium". Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 588–92. Bibcode:2000PNAS...97..588S. doi: 10.1073/pnas.97.2.588 . PMC   15374 . PMID   10639123.
  2. ↑ Dutt P, Spriggs CN, Davies PL, Jia Z, Elce JS (October 2002). "Origins of the difference in Ca2+ requirement for activation of mu- and m-calpain". The Biochemical Journal. 367 (Pt 1): 263–9. doi:10.1042/bj20020485. PMC   1222847 . PMID   12014988.
  3. 1 2 3 4 Ono Y, Sorimachi H (January 2012). "Calpains: an elaborate proteolytic system". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1824 (1): 224–36. doi: 10.1016/j.bbapap.2011.08.005 . PMID   21864727.
  4. ↑ Hosfield CM, Elce JS, Davies PL, Jia Z (December 1999). "Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation". The EMBO Journal. 18 (24): 6880–9. doi:10.1093/emboj/18.24.6880. PMC   1171751 . PMID   10601010.
  5. ↑ Dutt P, Arthur JS, Croall DE, Elce JS (October 1998). "m-Calpain subunits remain associated in the presence of calcium". FEBS Letters. 436 (3): 367–71. doi:10.1016/s0014-5793(98)01167-3. PMID   9801150.
  6. 1 2 Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL (March 2002). "A Ca(2+) switch aligns the active site of calpain". Cell. 108 (5): 649–60. doi: 10.1016/S0092-8674(02)00659-1 . PMID   11893336. S2CID   15607738.
  7. ↑ Chou JS, Impens F, Gevaert K, Davies PL (July 2011). "m-Calpain activation in vitro does not require autolysis or subunit dissociation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (7): 864–72. doi:10.1016/j.bbapap.2011.04.007. PMID   21549862.
  8. ↑ Liu Z, Cao J, Gao X, Ma Q, Ren J, Xue Y (April 2011). "GPS-CCD: a novel computational program for the prediction of calpain cleavage sites". PLOS ONE. 6 (4): e19001. Bibcode:2011PLoSO...619001L. doi: 10.1371/journal.pone.0019001 . PMC   3080405 . PMID   21533053.
  9. ↑ Breitwieser GE (2008). "Extracellular calcium as an integrator of tissue function". The International Journal of Biochemistry & Cell Biology. 40 (8): 1467–80. doi:10.1016/j.biocel.2008.01.019. PMC   2441573 . PMID   18328773.
  10. ↑ Hanna RA, Campbell RL, Davies PL (November 2008). "Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin". Nature. 456 (7220): 409–12. Bibcode:2008Natur.456..409H. doi:10.1038/nature07451. PMID   19020623. S2CID   4399656.
  11. ↑ Storr SJ, Carragher NO, Frame MC, Parr T, Martin SG (May 2011). "The calpain system and cancer". Nature Reviews. Cancer. 11 (5): 364–74. doi:10.1038/nrc3050. PMID   21508973. S2CID   23555255.
  12. ↑ Storr SJ, Safuan S, Woolston CM, Abdel-Fatah T, Deen S, Chan SY, Martin SG (October 2012). "Calpain-2 expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer". Journal of Cellular and Molecular Medicine. 16 (10): 2422–8. doi:10.1111/j.1582-4934.2012.01559.x. PMC   3472029 . PMID   22435971.
  13. ↑ Franco SJ, Huttenlocher A (September 2005). "Regulating cell migration: calpains make the cut". Journal of Cell Science. 118 (Pt 17): 3829–38. doi: 10.1242/jcs.02562 . PMID   16129881.
  14. ↑ Grieve S, Gao Y, Hall C, Hu J, Greer PA (August 2016). "Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis". Molecular and Cellular Biology. 36 (15): 2078–88. doi:10.1128/MCB.01062-15. PMC   4946432 . PMID   27215381.
  15. ↑ MacLeod JA, Gao Y, Hall C, Muller WJ, Gujral TS, Greer PA (September 2018). "Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib". Oncotarget. 9 (70): 33382–33395. doi:10.18632/oncotarget.26078. PMC   6161787 . PMID   30279968.
  16. ↑ "Structure and nomenclature / Calpain Research Portal: Calpain Structure and Nomenclature". calpain.net. Retrieved 2021-01-17.
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