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PDBsum entry 1hl4

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protein metals Protein-protein interface(s) links
Oxidoreductase PDB id
1hl4
Jmol
Contents
Protein chains
153 a.a. *
127 a.a. *
Metals
_ZN ×2
Waters ×311
* Residue conservation analysis
PDB id:
1hl4
Name: Oxidoreductase
Title: The structure of apo type human cu, zn superoxide dismutase
Structure: Superoxide dismutase. Chain: a, b, c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.
Biol. unit: Dimer (from PDB file)
Resolution:
1.82Å     R-factor:   0.234     R-free:   0.283
Authors: R.W.Strange,S.Antonyuk,M.A.Hough,P.Doucette,J.Rodriguez,P.J. L.J.Hayward,J.S.Valentine,S.S.Hasnain
Key ref:
R.W.Strange et al. (2003). The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. J Mol Biol, 328, 877-891. PubMed id: 12729761 DOI: 10.1016/S0022-2836(03)00355-3
Date:
13-Mar-03     Release date:   08-May-03    
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.
Protein chains
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
Seq:
Struc:
154 a.a.
127 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: 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: Fe cation or Mn(2+) or (Zn(2+) and Cu cation)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   17 terms 
  Biological process     reactive oxygen species metabolic process   60 terms 
  Biochemical function     antioxidant activity     12 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/S0022-2836(03)00355-3 J Mol Biol 328:877-891 (2003)
PubMed id: 12729761  
 
 
The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis.
R.W.Strange, S.Antonyuk, M.A.Hough, P.A.Doucette, J.A.Rodriguez, P.J.Hart, L.J.Hayward, J.S.Valentine, S.S.Hasnain.
 
  ABSTRACT  
 
Cu, Zn superoxide dismutase (SOD1) forms a crucial component of the cellular defence against oxidative stress. Zn-deficient wild-type and mutant human SOD1 have been implicated in the disease familial amyotrophic lateral sclerosis (FALS). We present here the crystal structures of holo and metal-deficient (apo) wild-type protein at 1.8A resolution. The P21 wild-type holo enzyme structure has nine independently refined dimers and these combine to form a "trimer of dimers" packing motif in each asymmetric unit. There is no significant asymmetry between the monomers in these dimers, in contrast to the subunit structures of the FALS G37R mutant of human SOD1 and in bovine Cu,Zn SOD. Metal-deficient apo SOD1 crystallizes with two dimers in the asymmetric unit and shows changes in the metal-binding sites and disorder in the Zn binding and electrostatic loops of one dimer, which is devoid of metals. The second dimer lacks Cu but has approximately 20% occupancy of the Zn site and remains structurally similar to wild-type SOD1. The apo protein forms a continuous, extended arrangement of beta-barrels stacked up along the short crystallographic b-axis, while perpendicular to this axis, the constituent beta-strands form a zig-zag array of filaments, the overall arrangement of which has a similarity to the common structure associated with amyloid-like fibrils.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. The arrangement of the two dimers in the asymmetric unit of apo wtSOD1. The positions of the disordered Zn-binding (residues 67/68-78) and electrostatic (residues 125-141) loops are indicated.
Figure 6.
Figure 6. The arrangement of the nine dimers in the asymmetric unit of P21 holo wtSOD1 (upper panel) and the five dimers in the asymmetic unit of C2221 wtSOD1 (lower panel; our own unpublished data, similar to that described by Parge et al.[36.] for this crystal form). The dimers are coloured differently as an aid to viewing. The trimer of dimers motif is evident. The electrostatic loop residues (128-131) involved in H-bonding interactions at the trimeric interfaces are highlighted in white.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 328, 877-891) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21104697 A.D.Schuyler, H.A.Carlson, and E.L.Feldman (2011).
Computational methods for identifying a layered allosteric regulatory mechanism for ALS-causing mutations of Cu-Zn superoxide dismutase 1.
  Proteins, 79, 417-427.  
20515426 J.Gamez, C.Caponnetto, L.Ferrera, E.Syriani, V.Marini, M.Morales, D.Bordo, C.Pirro, C.Garre, and P.Origone (2011).
I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families.
  Amyotroph Lateral Scler, 12, 70-75.  
20184893 C.Kayatekin, J.A.Zitzewitz, and C.R.Matthews (2010).
Disulfide-reduced ALS variants of Cu, Zn superoxide dismutase exhibit increased populations of unfolded species.
  J Mol Biol, 398, 320-331.  
20232802 R.J.Nowak, G.D.Cuny, S.Choi, P.T.Lansbury, and S.S.Ray (2010).
Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods.
  J Med Chem, 53, 2709-2718.  
19805550 A.Durazo, B.F.Shaw, M.Chattopadhyay, K.F.Faull, A.M.Nersissian, J.S.Valentine, and J.P.Whitelegge (2009).
Metal-free superoxide dismutase-1 and three different amyotrophic lateral sclerosis variants share a similar partially unfolded beta-barrel at physiological temperature.
  J Biol Chem, 284, 34382-34389.  
19800308 A.Galaleldeen, R.W.Strange, L.J.Whitson, S.V.Antonyuk, N.Narayana, A.B.Taylor, J.P.Schuermann, S.P.Holloway, S.S.Hasnain, and P.J.Hart (2009).
Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A.
  Arch Biochem Biophys, 492, 40-47.
PDB codes: 2wko 3gzo 3gzp 3gzq
19651777 A.Tiwari, A.Liba, S.H.Sohn, S.V.Seetharaman, O.Bilsel, C.R.Matthews, P.J.Hart, J.S.Valentine, and L.J.Hayward (2009).
Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis.
  J Biol Chem, 284, 27746-27758.  
19023603 D.C.Soares, P.N.Barlow, D.J.Porteous, and R.S.Devon (2009).
An interrupted beta-propeller and protein disorder: structural bioinformatics insights into the N-terminus of alsin.
  J Mol Model, 15, 113-122.  
19227972 D.D.Winkler, J.P.Schuermann, X.Cao, S.P.Holloway, D.R.Borchelt, M.C.Carroll, J.B.Proescher, V.C.Culotta, and P.J.Hart (2009).
Structural and biophysical properties of the pathogenic SOD1 variant H46R/H48Q.
  Biochemistry, 48, 3436-3447.
PDB code: 3gqf
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.  
19828437 K.Teilum, M.H.Smith, E.Schulz, L.C.Christensen, G.Solomentsev, M.Oliveberg, and M.Akke (2009).
Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization.
  Proc Natl Acad Sci U S A, 106, 18273-18278.  
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
19271992 M.Chattopadhyay, and J.S.Valentine (2009).
Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS.
  Antioxid Redox Signal, 11, 1603-1614.  
19751676 T.Schmidlin, B.K.Kennedy, and V.Daggett (2009).
Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.
  Biophys J, 97, 1709-1718.  
18840448 C.Kayatekin, J.A.Zitzewitz, and C.R.Matthews (2008).
Zinc binding modulates the entire folding free energy surface of human Cu,Zn superoxide dismutase.
  J Mol Biol, 384, 540-555.  
19052230 F.Ding, and N.V.Dokholyan (2008).
Dynamical roles of metal ions and the disulfide bond in Cu, Zn superoxide dismutase folding and aggregation.
  Proc Natl Acad Sci U S A, 105, 19696-19701.  
18666828 Q.Wang, J.L.Johnson, N.Y.Agar, and J.N.Agar (2008).
Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival.
  PLoS Biol, 6, e170.  
18378676 X.Cao, S.V.Antonyuk, S.V.Seetharaman, L.J.Whitson, A.B.Taylor, S.P.Holloway, R.W.Strange, P.A.Doucette, J.S.Valentine, A.Tiwari, L.J.Hayward, S.Padua, J.A.Cohlberg, S.S.Hasnain, and P.J.Hart (2008).
Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis.
  J Biol Chem, 283, 16169-16177.
PDB codes: 2vr6 2vr7 2vr8 3cqp 3cqq
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
18025602 I.Hadji, M.N.Marzouki, D.Ferraro, E.Fasano, H.Majdoub, G.Pani, and F.Limam (2007).
Purification and characterization of a Cu,Zn-SOD from garlic (Allium sativum L.). Antioxidant effect on tumoral cell lines.
  Appl Biochem Biotechnol, 143, 129-141.  
17548825 R.W.Strange, C.W.Yong, W.Smith, and S.S.Hasnain (2007).
Molecular dynamics using atomic-resolution structure reveal structural fluctuations that may lead to polymerization of human Cu-Zn superoxide dismutase.
  Proc Natl Acad Sci U S A, 104, 10040-10044.
PDB code: 2v0a
16798882 A.Nordlund, and M.Oliveberg (2006).
Folding of Cu/Zn superoxide dismutase suggests structural hotspots for gain of neurotoxic function in ALS: parallels to precursors in amyloid disease.
  Proc Natl Acad Sci U S A, 103, 10218-10223.  
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.  
16880213 M.C.Carroll, C.E.Outten, J.B.Proescher, L.Rosenfeld, W.H.Watson, L.J.Whitson, P.J.Hart, L.T.Jensen, and V.Cizewski Culotta (2006).
The effects of glutaredoxin and copper activation pathways on the disulfide and stability of Cu,Zn superoxide dismutase.
  J Biol Chem, 281, 28648-28656.  
16488975 S.D.Khare, and N.V.Dokholyan (2006).
Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants.
  Proc Natl Acad Sci U S A, 103, 3147-3152.  
16771675 Y.Furukawa, and T.V.O'Halloran (2006).
Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis.
  Antioxid Redox Signal, 8, 847-867.  
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.  
15755678 C.Cheroni, M.Peviani, P.Cascio, S.Debiasi, C.Monti, and C.Bendotti (2005).
Accumulation of human SOD1 and ubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron disease progression correlates with a decrease of proteasome.
  Neurobiol Dis, 18, 509-522.  
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.  
15987780 M.J.Lindberg, R.Byström, N.Boknäs, P.M.Andersen, and M.Oliveberg (2005).
Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants.
  Proc Natl Acad Sci U S A, 102, 9754-9759.  
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.  
16045483 S.H.Koh, Y.B.Lee, K.S.Kim, H.J.Kim, M.Kim, Y.J.Lee, J.Kim, K.W.Lee, and S.H.Kim (2005).
Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene.
  Eur J Neurosci, 22, 301-309.  
15799963 Y.J.Kim, R.Nakatomi, T.Akagi, T.Hashikawa, and R.Takahashi (2005).
Unsaturated fatty acids induce cytotoxic aggregate formation of amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants.
  J Biol Chem, 280, 21515-21521.  
15062777 A.F.Miller (2004).
Superoxide dismutases: active sites that save, but a protein that kills.
  Curr Opin Chem Biol, 8, 162-168.  
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
15198682 M.Urushitani, J.Kurisu, M.Tateno, S.Hatakeyama, K.Nakayama, S.Kato, and R.Takahashi (2004).
CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70.
  J Neurochem, 90, 231-244.  
15485869 P.A.Doucette, L.J.Whitson, X.Cao, V.Schirf, B.Demeler, J.S.Valentine, J.C.Hansen, and P.J.Hart (2004).
Dissociation of human copper-zinc superoxide dismutase dimers using chaotrope and reductant. Insights into the molecular basis for dimer stability.
  J Biol Chem, 279, 54558-54566.  
12754496 J.S.Elam, A.B.Taylor, R.Strange, S.Antonyuk, P.A.Doucette, J.A.Rodriguez, S.S.Hasnain, L.J.Hayward, J.S.Valentine, T.O.Yeates, and P.J.Hart (2003).
Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS.
  Nat Struct Biol, 10, 461-467.
PDB codes: 1oez 1ozt 1ozu
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.