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Calpain

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<StructureSection load='1zcm' size='400' side='right' caption='Human calpain1 large subunit complex with inhibitor and Ca+2 ions (PDB entry [[1zcm]])' scene=''>
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<StructureSection load='1zcm' size='350' side='right' caption='Human calpain1 large subunit complex with inhibitor and Ca+2 ions (green) (PDB entry [[1zcm]])' scene='51/517369/Cv/1'>
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__NOTOC__
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__TOC__
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'''Calpains''' (CAP) are calcium-dependent cysteine proteases. The CAP family contains 14 members. CAP is a heterodimer containing a small28kDa regulatory subunit which is identical for all CAPs and a large 80kDa catalytic subunit. The best characterized CAPs are CAP1 (or mu-CAP) and CAP2 (or M-CAP). CAP7 is atypical CAP that lacks a penta-EF-hand domain. CAP8 and CAP9 are involved in the mucosal defense against stress-induced gastropathies. CAP9 has been identified as the tumor suppressor for gastric cancer. CAP13 is expressed in testis and lungs. CAPs are regulated by Ca+2 concentration, phosphorylation and calpastatin.
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== Function ==
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==3D structures of calpain==
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'''Calpains''' (CAP) are calcium-dependent cysteine proteases. CAPs are regulated by Ca+2 concentration, phosphorylation and calpastatin.<ref>PMID:12843408</ref> The CAP family contains 14 members.<br />
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* '''CAP1''' (or mu-CAP) and '''CAP2''' (or M-CAP) T are the best characterized CAPs. <br />
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* '''CAP2''' limits the extent of neuronal plasticity and learning<ref>PMID:33339205</ref>.
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* '''CAP3''' is expressed in skeletal muscles and regulates sarcomere remodelling<ref>PMID:16884488</ref>.
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* '''CAP7''' is atypical CAP that lacks a penta-EF-hand domain.<br />
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* '''CAP8''' and '''CAP9''' are involved in the mucosal defense against stress-induced gastropathies.<br />
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* '''CAP9''' has been identified as the tumor suppressor for gastric cancer.<br />
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* '''CAP13''' is expressed in testis and lungs.
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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==Disease==
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===CAP small subunit===
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CAP3 defects lead to a certain muscular dystrophy. Defective CAPs have a role in neurodegeneration.
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[[1aj5 ]]– rCAP domain VI – rat<br />
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== Structural highlights ==
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[[1dvi]] - rCAP domain VI + Ca<br />
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[[1np8]] – rCAP residues 87-245 - Cd<br />
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[[1alv]], [[1nx2]] - pCAP domain VI + Ca – pig<br />
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[[1alw]], [[1nx3]] - pCAP domain VI + Ca+ inhibitor<br />
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[[1nx0]] - pCAP domain VI + Ca+ Calpastatin peptide + small molecule inhibitor peptide<br />
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[[1nx1]] - pCAP domain VI + Ca+ Calpastatin peptide<br />
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===CAP1===
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CAP is a heterodimer containing a small 28kDa regulatory subunit which is identical for all CAPs and a large 80kDa catalytic subunit. CAP undergoes conformational change upon binding of Ca+2 ions resulting in closing of its active site cleft and activation as a cysteine protease. <ref>PMID:11893336</ref>
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*<scene name='51/517369/Cv/7'>Inhibitor binding site</scene>. Water molecules are shown as red spheres.
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*<scene name='51/517369/Cv/8'>Covalent bond between Cys 115 of human calpain1 large subunit with inhibitor</scene>.
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*<scene name='51/517369/Cv/4'>1st Ca+2 coordination site</scene>.
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*<scene name='51/517369/Cv/5'>2nd Ca+2 coordination site</scene>.<ref>PMID:16411745</ref>
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[[1kxr]], [[1tlo]], [[1qxp]] - rCAP protease domain + Ca<br />
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==3D structures of calpain==
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[[1tl9]] - rCAP protease domain + Ca+ leupeptin inhibitor<br />
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[[Calpain 3D structures]]
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[[2g8e]], [[2g8j]], [[2nqg]], [[2nqi]], [[2r9c]], [[2r9f]] - rCAP protease domain + Ca+ inhibitor<br />
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[[2ary]] - hCAP protease domain + Ca – human<br />
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[[1zcm]] - hCAP protease domain (mutant) + Ca+ inhibitor<br />
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===CAP2===
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</StructureSection>
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[[1mdw]] – rCAP2 protease core domain I and II (mutant) + Ca<br />
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== References ==
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[[1df0]], [[1u5i]] – rCAP small subunit domain VI + rCAP2 large subunit<br />
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<references/>
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[[3df0]] - hCAP small subunit + hCAP2 large subunit + Calpastatin + Ca<br />
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[[3bow]] - rCAP small subunit + rCAP2 large subunit + Calpastatin + Ca<br />
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[[1kfu]], [[1kfx]] – hCAP small subunit + hCAP2 large subunit
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===CAP7===
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[[2qfe]] - hCAP C2-like domain
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===CAP8===
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[[2nqa]] - hCAP protease domain + Ca+ leupeptin inhibitor<br />
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===CAP9===
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[[1ziv]] – hCAP catalytic domain<br />
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[[2p0r]] - hCAP protease domain + Ca+ leupeptin inhibitor<br />
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===CAP13===
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[[2i7a]] – hCAP domain IV + Ca<br />
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</StructureSection>
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[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Human calpain1 large subunit complex with inhibitor and Ca+2 ions (green) (PDB entry 1zcm)

Drag the structure with the mouse to rotate

References

  1. ↑ Goll DE, Thompson VF, Li H, Wei W, Cong J. The calpain system. Physiol Rev. 2003 Jul;83(3):731-801. PMID:12843408 doi:http://dx.doi.org/10.1152/physrev.00029.2002
  2. ↑ Wang Y, Liu Y, Bi X, Baudry M. Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death. Cells. 2020 Dec 16;9(12):2698. PMID:33339205 doi:10.3390/cells9122698
  3. ↑ Duguez S, Bartoli M, Richard I. Calpain 3: a key regulator of the sarcomere? FEBS J. 2006 Aug;273(15):3427-36. PMID:16884488 doi:10.1111/j.1742-4658.2006.05351.x
  4. ↑ Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL. A Ca(2+) switch aligns the active site of calpain. Cell. 2002 Mar 8;108(5):649-60. PMID:11893336
  5. ↑ Li Q, Hanzlik RP, Weaver RF, Schonbrunn E. Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core. Biochemistry. 2006 Jan 24;45(3):701-8. PMID:16411745 doi:http://dx.doi.org/10.1021/bi052077b

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Michal Harel, Alexander Berchansky

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