Calpain: Difference between revisions

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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=''>
<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'>
__NOTOC__
__TOC__
'''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.
== Function ==


==3D structures of calpain==
'''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 />
*  '''CAP1''' (or mu-CAP) and '''CAP2''' (or M-CAP) T are the best characterized CAPs. <br />
*  '''CAP2''' limits the extent of neuronal plasticity and learning<ref>PMID:33339205</ref>.
*  '''CAP3''' is expressed in skeletal muscles and regulates sarcomere remodelling<ref>PMID:16884488</ref>.
*  '''CAP7''' is atypical CAP that lacks a penta-EF-hand domain.<br />
*  '''CAP8''' and '''CAP9''' are involved in the mucosal defense against stress-induced gastropathies.<br />
*  '''CAP9''' has been identified as the tumor suppressor for gastric cancer.<br />
*  '''CAP13''' is expressed in testis and lungs.   


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
==Disease==


===CAP small subunit===
CAP3 defects lead to a certain muscular dystrophy.  Defective CAPs have a role in neurodegeneration.


[[1aj5 ]]– rCAP domain VI – rat<br />
== Structural highlights ==
[[1dvi]] - rCAP domain VI + Ca<br />
[[1np8]] – rCAP residues 87-245 - Cd<br />
[[1alv]], [[1nx2]] - pCAP domain VI + Ca – pig<br />
[[1alw]], [[1nx3]] - pCAP domain VI + Ca+ inhibitor<br />
[[1nx0]] - pCAP domain VI + Ca+ Calpastatin peptide + small molecule inhibitor peptide<br />
[[1nx1]] - pCAP domain VI + Ca+ Calpastatin peptide<br />


===CAP1===
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>
*<scene name='51/517369/Cv/7'>Inhibitor binding site</scene>. Water molecules are shown as red spheres.
*<scene name='51/517369/Cv/8'>Covalent bond between Cys 115 of human calpain1 large subunit with inhibitor</scene>.
*<scene name='51/517369/Cv/4'>1st Ca+2 coordination site</scene>.
*<scene name='51/517369/Cv/5'>2nd Ca+2 coordination site</scene>.<ref>PMID:16411745</ref>


[[1kxr]], [[1tlo]], [[1qxp]] - rCAP protease domain + Ca<br />
==3D structures of calpain==
[[1tl9]] - rCAP protease domain + Ca+ leupeptin inhibitor<br />
[[Calpain 3D structures]]
[[2g8e]], [[2g8j]], [[2nqg]], [[2nqi]], [[2r9c]], [[2r9f]] - rCAP protease domain + Ca+ inhibitor<br />
[[2ary]] - hCAP protease domain + Ca – human<br />
[[1zcm]] - hCAP protease domain (mutant) + Ca+ inhibitor<br />


===CAP2===
</StructureSection>


[[1mdw]] – rCAP2 protease core domain I and II (mutant) + Ca<br />
== References ==
[[1df0]], [[1u5i]] – rCAP small subunit domain VI + rCAP2 large subunit<br />
<references/>
[[3df0]] - hCAP small subunit + hCAP2 large subunit + Calpastatin + Ca<br />
[[3bow]] - rCAP small subunit + rCAP2 large subunit + Calpastatin + Ca<br />
[[1kfu]], [[1kfx]] – hCAP small subunit + hCAP2 large subunit
 
===CAP7===
 
[[2qfe]] - hCAP C2-like domain
 
===CAP8===
 
[[2nqa]] - hCAP protease domain + Ca+ leupeptin inhibitor<br />
 
===CAP9===
 
[[1ziv]] – hCAP catalytic domain<br />
[[2p0r]] - hCAP protease domain + Ca+ leupeptin inhibitor<br />
 
===CAP13===
 
[[2i7a]] – hCAP domain IV + Ca<br />
 
</StructureSection>
[[Category:Topic Page]]
[[Category:Topic Page]]

Latest revision as of 10:19, 2 June 2024

Function

Calpains (CAP) are calcium-dependent cysteine proteases. CAPs are regulated by Ca+2 concentration, phosphorylation and calpastatin.[1] The CAP family contains 14 members.

  • CAP1 (or mu-CAP) and CAP2 (or M-CAP) T are the best characterized CAPs.
  • CAP2 limits the extent of neuronal plasticity and learning[2].
  • CAP3 is expressed in skeletal muscles and regulates sarcomere remodelling[3].
  • 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.

Disease

CAP3 defects lead to a certain muscular dystrophy. Defective CAPs have a role in neurodegeneration.

Structural highlights

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. [4]

  • . Water molecules are shown as red spheres.
  • .
  • .
  • .[5]

3D structures of calpain

Calpain 3D structures


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

Drag the structure with the mouse to rotate

ReferencesReferences

  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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