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PDBsum entry 1mdw

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protein metals Protein-protein interface(s) links
Hydrolase PDB id
1mdw
Jmol
Contents
Protein chains
319 a.a. *
Metals
_CA ×4
Waters ×365
* Residue conservation analysis
PDB id:
1mdw
Name: Hydrolase
Title: Crystal structure of calcium-bound protease core of calpain ii reveals the basis for intrinsic inactivation
Structure: Calpain ii, catalytic subunit. Chain: a, b. Fragment: protease core domains i and ii (residues 17-346). Synonym: calcium-activated neutral proteinase, canp, m- type, m-calpain, millimolar-calpain. Engineered: yes. Mutation: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: calpain ii. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.95Å     R-factor:   0.207     R-free:   0.243
Authors: T.Moldoveanu,C.M.Hosfield,D.Lim,Z.Jia,P.L.Davies
Key ref:
T.Moldoveanu et al. (2003). Calpain silencing by a reversible intrinsic mechanism. Nat Struct Biol, 10, 371-378. PubMed id: 12665854 DOI: 10.1038/nsb917
Date:
07-Aug-02     Release date:   29-Apr-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q07009  (CAN2_RAT) -  Calpain-2 catalytic subunit
Seq:
Struc:
 
Seq:
Struc:
700 a.a.
319 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.4.22.53  - Calpain-2.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Cofactor: Ca(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     regulation of cytoskeleton organization   2 terms 
  Biochemical function     calcium ion binding     2 terms  

 

 
DOI no: 10.1038/nsb917 Nat Struct Biol 10:371-378 (2003)
PubMed id: 12665854  
 
 
Calpain silencing by a reversible intrinsic mechanism.
T.Moldoveanu, C.M.Hosfield, D.Lim, Z.Jia, P.L.Davies.
 
  ABSTRACT  
 
Uncontrolled activation of calpain can lead to necrotic cell death and irreversible tissue damage. We have discovered an intrinsic mechanism whereby the autolysis-generated protease core fragment of calpain is inactivated through the inherent instability of a key alpha-helix. This auto-inactivation state was captured by the 1.9 A Ca(2+)-bound structure of the protease core from m-calpain, and sequence alignments suggest that it applies to about half of the calpain isoforms. Intact calpain large subunits are also subject to this inhibition, which can be prevented through assembly of the heterodimers. Other isoforms or their released cores are not silenced by this mechanism and might contribute to calpain patho-physiologies.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structural comparison of the calcium-bound - and m-minicalpains. a, Overlap of mI-II onto I-II using ALIGN30. Gold spheres indicate Ca^2+ ions. The protease core of mI-II (red/pink) is superimposed on I-II (transparent blue/cyan). -strands and -helices are numbered sequentially from the N terminus (N) to the C terminus (C). The side chain atoms of the catalytic triad residues are colored in red (oxygen), dark blue (nitrogen) and gray (carbon), and the bonds have the domain color. b, Stereo view of the mI-II region showing oxygen coordinations to DI Ca^2+ (eight) and DII Ca^2+ (pentagonal bipyramid), as well as the double salt bridge between Arg94 and Glu323. Side chains are structured exactly as predicted from the Ca^2+-bound I-II structure.
Figure 4.
Figure 4. Hydrophobic core collapses in mI-II but not in I-II. The hydrophobic core stabilized by helix 7 is shown for the two minicalpains. The color scheme is the same as that in Fig. 2, with Phe207/217 and Trp106/116 shown in green and pink, respectively. a, Stereo view of mI-II core. The helix-breaking Gly 203 is orange. b, Stereo view of the I-II core. The peptide 207 -213 (yellow ribbon) is structured in I-II because Ala 213 (orange) stabilizes helix 7.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 371-378) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21030783 H.Sorimachi, S.Hata, and Y.Ono (2010).
Expanding members and roles of the calpain superfamily and their genetically modified animals.
  Exp Anim, 59, 549-566.  
19020622 T.Moldoveanu, K.Gehring, and D.R.Green (2008).
Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains.
  Nature, 456, 404-408.
PDB code: 3df0
17651432 A.Fernández-Montalván, T.Bouwmeester, G.Joberty, R.Mader, M.Mahnke, B.Pierrat, J.M.Schlaeppi, S.Worpenberg, and B.Gerhartz (2007).
Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.
  FEBS J, 274, 4256-4270.  
17218315 D.Cuerrier, T.Moldoveanu, R.L.Campbell, J.Kelly, B.Yoruk, S.H.Verhelst, D.Greenbaum, M.Bogyo, and P.L.Davies (2007).
Development of calpain-specific inactivators by screening of positional scanning epoxide libraries.
  J Biol Chem, 282, 9600-9611.
PDB codes: 2nqg 2nqi
17942392 R.L.Mellgren, and X.Huang (2007).
Fetuin A stabilizes m-calpain and facilitates plasma membrane repair.
  J Biol Chem, 282, 35868-35877.  
17646163 S.Hata, N.Doi, F.Kitamura, and H.Sorimachi (2007).
Stomach-specific calpain, nCL-2/calpain 8, is active without calpain regulatory subunit and oligomerizes through C2-like domains.
  J Biol Chem, 282, 27847-27856.  
16803906 E.Melloni, M.Averna, R.Stifanese, R.De Tullio, E.Defranchi, F.Salamino, and S.Pontremoli (2006).
Association of calpastatin with inactive calpain: a novel mechanism to control the activation of the protease?
  J Biol Chem, 281, 24945-24954.  
16542156 J.Joy, N.Nalabothula, M.Ghosh, O.Popp, M.Jochum, W.Machleidt, S.Gil-Parrado, and T.A.Holak (2006).
Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19(INK4d).
  Biol Chem, 387, 329-335.  
16623703 M.Averna, R.Stifanese, R.De Tullio, E.Defranchi, F.Salamino, E.Melloni, and S.Pontremoli (2006).
Interaction between catalytically inactive calpain and calpastatin. Evidence for its occurrence in stimulated cells.
  FEBS J, 273, 1660-1668.  
14581465 T.Moldoveanu, Z.Jia, and P.L.Davies (2004).
Calpain activation by cooperative Ca2+ binding at two non-EF-hand sites.
  J Biol Chem, 279, 6106-6114.  
14656436 G.P.Pal, T.De Veyra, J.S.Elce, and Z.Jia (2003).
Crystal structure of a micro-like calpain reveals a partially activated conformation with low Ca2+ requirement.
  Structure, 11, 1521-1526.
PDB code: 1qxp
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.