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Oxidoreductase PDB id
1n19
Jmol
Contents
Protein chains
153 a.a. *
Ligands
SO4
Metals
_ZN ×2
CU1 ×2
Waters ×262
* Residue conservation analysis
PDB id:
1n19
Name: Oxidoreductase
Title: Structure of the hsod a4v mutant
Structure: Superoxide dismutase [cu-zn]. Chain: a, b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
Resolution:
1.86Å     R-factor:   0.207     R-free:   0.260
Authors: R.M.F.Cardoso,M.M.Thayer,M.Didonato,T.P.Lo,C.K.Bruns, E.D.Getzoff,J.A.Tainer
Key ref:
R.M.Cardoso et al. (2002). Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase. J Mol Biol, 324, 247-256. PubMed id: 12441104 DOI: 10.1016/S0022-2836(02)01090-2
Date:
16-Oct-02     Release date:   27-Nov-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
Seq:
Struc: 		154 a.a.
153 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.15.1.1  - Superoxide dismutase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 superoxide + 2 H+ = O2 + H2O2
2 × superoxide
 + 2 × H(+)
 = O(2)
 + H(2)O(2)
      Cofactor: Iron or manganese or (zinc and copper)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   15 terms 
  Biological process     aging   57 terms 
  Biochemical function     antioxidant activity     10 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/S0022-2836(02)01090-2 J Mol Biol 324:247-256 (2002)
PubMed id: 12441104  
 
 
Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase.
R.M.Cardoso, M.M.Thayer, M.DiDonato, T.P.Lo, C.K.Bruns, E.D.Getzoff, J.A.Tainer.
 
  ABSTRACT  
 
Mutations in human superoxide dismutase (HSOD) have been linked to the familial form of amyotrophic lateral sclerosis (FALS). Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is one of the most common neurodegenerative disorders in humans. In ALS patients, selective killing of motor neurons leads to progressive paralysis and death within one to five years of onset. The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with the most rapid disease progression. Here we identify and characterize key differences in the stability between the A4V mutant protein and its thermostable parent (HSOD-AS), in which free cysteine residues were mutated to eliminate interferences from cysteine oxidation. Denaturation studies reveal that A4V unfolds at a guanidine-HCl concentration 1M lower than HSOD-AS, revealing that A4V is significantly less stable than HSOD-AS. Determination and analysis of the crystallographic structures of A4V and HSOD-AS reveal structural features likely responsible for the loss of architectural stability of A4V observed in the denaturation experiments. The combined structural and biophysical results presented here argue that architectural destabilization of the HSOD protein may underlie the toxic function of the many HSOD FALS mutations.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Stereo views of A4V and HSOD-AS structures and electron density maps. Electron density F[o] -F[c] omit maps near the Ala4->Val mutation site in the A4V and HSOD-AS structures were contoured at 4.0s (blue cages). (a) Electron density maps near Ala4 (yellow) in the HSOD-AS structure. (b) Electron density maps near Val4 (purple) in the A4V structure. Orange residues Phe20, Leu106, and Ile113 moved upon the Ala4->Val mutation. 		Figure 3.
Figure 3. Structural comparison of the superposed A4V and HSOD-AS structures. (a) Overall superposition of the A chains of the A4V and HSOD-AS molecules. The C^a atoms of the b-strand regions of the A chains of HSOD-AS (green) and the A chain of A4V (red) superpose well. The subunit that was not superposed in the A4V (red) structure falls in the middle of the subunits of each HSOD-AS dimer that were not superposed (blue). The active site region is indicated by the copper (gold) and zinc (gray). The mutation site, residue 4, is shown in the A4V (Val4, yellow) and HSOD-AS (Ala4, purple). (b) Superposition of the active site in A4V (pink) and HSOD-AS (green). The metal-ligand bonds (lavender spheres) are from Cu(I) to His46, His48, and His120, and from Zn(II) to His63, His71, His80 and Asp83.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 324, 247-256) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20094844 S.Karaer, C.Tarhan, M.Pekmez, I.Hamad, N.Arda, and A.T.Sarikaya (2010).
Expression of human A4V mutant Cu,Zn superoxide dismutase in Schizosaccharomyces pombe: investigations of its toxic properties.
  Biochem Genet, 48, 113-124.  
19063897 D.S.Shin, M.Didonato, D.P.Barondeau, G.L.Hura, C.Hitomi, J.A.Berglund, E.D.Getzoff, S.C.Cary, and J.A.Tainer (2009).
Superoxide dismutase from the eukaryotic thermophile Alvinella pompejana: structures, stability, mechanism, and insights into amyotrophic lateral sclerosis.
  J Mol Biol, 385, 1534-1555.
PDB codes: 3f7k 3f7l
19265433 J.J.Perry, A.S.Hearn, D.E.Cabelli, H.S.Nick, J.A.Tainer, and D.N.Silverman (2009).
Contribution of human manganese superoxide dismutase tyrosine 34 to structure and catalysis.
  Biochemistry, 48, 3417-3424.
PDB codes: 1zsp 1zte 1zuq 2p4k
19635794 K.S.Molnar, N.M.Karabacak, J.L.Johnson, Q.Wang, A.Tiwari, L.J.Hayward, S.J.Coales, Y.Hamuro, and J.N.Agar (2009).
A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop.
  J Biol Chem, 284, 30965-30973.  
19369197 L.Banci, I.Bertini, M.Boca, V.Calderone, F.Cantini, S.Girotto, and M.Vieru (2009).
Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.
  Proc Natl Acad Sci U S A, 106, 6980-6985.
PDB codes: 3ecu 3ecv 3ecw
17150313 B.Dash, R.Metz, H.J.Huebner, W.Porter, and T.D.Phillips (2007).
Molecular characterization of two superoxide dismutases from Hydra vulgaris.
  Gene, 387, 93.  
17888947 B.R.Roberts, J.A.Tainer, E.D.Getzoff, D.A.Malencik, S.R.Anderson, V.C.Bomben, K.R.Meyers, P.A.Karplus, and J.S.Beckman (2007).
Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS.
  J Mol Biol, 373, 877-890.
PDB code: 2r27
16644738 B.F.Shaw, A.Durazo, A.M.Nersissian, J.P.Whitelegge, K.F.Faull, and J.S.Valentine (2006).
Local unfolding in a destabilized, pathogenic variant of superoxide dismutase 1 observed with H/D exchange and mass spectrometry.
  J Biol Chem, 281, 18167-18176.  
16516535 P.J.Hart (2006).
Pathogenic superoxide dismutase structure, folding, aggregation and turnover.
  Curr Opin Chem Biol, 10, 131-138.  
15958382 A.Tiwari, Z.Xu, and L.J.Hayward (2005).
Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis.
  J Biol Chem, 280, 29771-29779.  
15952898 J.S.Valentine, P.A.Doucette, and S.Zittin Potter (2005).
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
  Annu Rev Biochem, 74, 563-593.  
15522870 N.Fujiwara, Y.Miyamoto, K.Ogasahara, M.Takahashi, T.Ikegami, R.Takamiya, K.Suzuki, and N.Taniguchi (2005).
Different immunoreactivity against monoclonal antibodies between wild-type and mutant copper/zinc superoxide dismutase linked to amyotrophic lateral sclerosis.
  J Biol Chem, 280, 5061-5070.  
15840828 S.Antonyuk, J.S.Elam, M.A.Hough, R.W.Strange, P.A.Doucette, J.A.Rodriguez, L.J.Hayward, J.S.Valentine, P.J.Hart, and S.S.Hasnain (2005).
Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg.
  Protein Sci, 14, 1201-1213.  
15019975 B.Leinweber, E.Barofsky, D.F.Barofsky, V.Ermilov, K.Nylin, and J.S.Beckman (2004).
Aggregation of ALS mutant superoxide dismutase expressed in Escherichia coli.
  Free Radic Biol Med, 36, 911-918.  
15056757 M.A.Hough, J.G.Grossmann, S.V.Antonyuk, R.W.Strange, P.A.Doucette, J.A.Rodriguez, L.J.Whitson, P.J.Hart, L.J.Hayward, J.S.Valentine, and S.S.Hasnain (2004).
Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.
  Proc Natl Acad Sci U S A, 101, 5976-5981.
PDB codes: 1uxl 1uxm
15079068 S.S.Ray, and P.T.Lansbury (2004).
A possible therapeutic target for Lou Gehrig's disease.
  Proc Natl Acad Sci U S A, 101, 5701-5702.  
12864925 C.M.Higgins, C.Jung, and Z.Xu (2003).
ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes.
  BMC Neurosci, 4, 16.  
12655070 J.S.Valentine, and P.J.Hart (2003).
Misfolded CuZnSOD and amyotrophic lateral sclerosis.
  Proc Natl Acad Sci U S A, 100, 3617-3622.  
12773627 P.B.Stathopulos, J.A.Rumfeldt, G.A.Scholz, R.A.Irani, H.E.Frey, R.A.Hallewell, J.R.Lepock, and E.M.Meiering (2003).
Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro.
  Proc Natl Acad Sci U S A, 100, 7021-7026.  
  12957544 R.E.Steward, M.W.MacArthur, R.A.Laskowski, and J.M.Thornton (2003).
Molecular basis of inherited diseases: a structural perspective.
  Trends Genet, 19, 505-513.  
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 codes are shown on the right.