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PDBsum entry 1ptz

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1ptz
Jmol
Contents
Protein chain
153 a.a. *
Ligands
SO4
Metals
_ZN ×2
CU1 ×2
Waters ×221
* Residue conservation analysis
PDB id:
1ptz
Name: Oxidoreductase
Title: Crystal structure of the human cu, zn superoxide dismutase, familial amyotrophic lateral sclerosis (fals) mutant h43r
Structure: Superoxide dismutase [cu-zn]. Chain: a, b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
1.80Å     R-factor:   0.186     R-free:   0.215
Authors: M.Didonato,L.Craig,M.E.Huff,M.M.Thayer,R.M.F.Cardoso, C.J.Kassmann,T.P.Lo,C.K.Bruns,E.T.Powers,J.W.Kelly, E.D.Getzoff,J.A.Tainer
Key ref:
M.DiDonato et al. (2003). ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. J Mol Biol, 332, 601-615. PubMed id: 12963370 DOI: 10.1016/S0022-2836(03)00889-1
Date:
23-Jun-03     Release date:   09-Sep-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.*
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   16 terms 
  Biological process     reactive oxygen species metabolic process   62 terms 
  Biochemical function     antioxidant activity     12 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/S0022-2836(03)00889-1 J Mol Biol 332:601-615 (2003)
PubMed id: 12963370  
 
 
ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization.
M.DiDonato, L.Craig, M.E.Huff, M.M.Thayer, R.M.Cardoso, C.J.Kassmann, T.P.Lo, C.K.Bruns, E.T.Powers, J.W.Kelly, E.D.Getzoff, J.A.Tainer.
 
  ABSTRACT  
 
Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Structural features of wild-type and FALS mutant human Cu,Zn SODs. A, FALS mutation sites (spheres), occur throughout the Cu,Zn SOD sequence, but are positioned in three dimensions at sites expected to impact the integrity of the b-barrel, especially the packing within the b-barrel ends or cork regions (purple), the dimer interface (blue) and other framework features (gray). B, Overall structural comparison by superposition of the H43R (red trace) and the wild-type represented by HSOD-AS (blue and green C^a traces). One subunit of each of the five HSOD-AS dimers (blue) was superposed onto one subunit of the H43R dimer (red). The other H43R subunit is amongst the HSOD-AS subunits that were not superposed (green). The conserved disulfide bond (yellow tubes) and the L106 and L38 hydrophobic "corks" (magenta tubes) are critical for stability of the protein and assembly specificity. The H43R mutation (upper right) is near the L38 cork and above the active-site Cu (bronze) and Zn (gray) shown with their seven ligands (red tubes with blue nitrogen and red oxygen atoms as spheres). C, The L38 cork region of HSOD-AS viewed down the b-barrel axis showing the importance of H43 (green) to the packing that stabilizes the b-barrel. Rim residues (gray) and the L38 cork (purple) are shown by van der Waals surfaces.
Figure 3.
Figure 3. Stereo pairs showing structural changes at the SOD H43R mutation site. A, Hydrogen-bonding pattern of H43 in HSOD-AS. H43 and residues hydrogen bonding to it are depicted with dark blue tubes, while metal ligands and the L38 cork are depicted with green tubes. Hydrogen bonds are depicted as dotted gold lines. B, Hydrogen-bonding pattern of R43 in H43R. R43 and residues hydrogen-bonded to it are depicted with red tubes. The H43R mutation results in the loss of a hydrogen bond to H120, which is a copper ligand. C, Increase in solvent accessibility of the L38 cork as a result of the H43R mutation. Differences between the molecular surface around HSOD-AS H43 (blue) and H43R R43 (pink) reveal the increased solvent accessibility of the L38 side-chain. Metal ligands and the L38 cork (green tubes), are adjacent to H43 (blue tubes) and impacted by the R43 mutation (red tubes).
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 332, 601-615) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23396808 S.Classen, G.L.Hura, J.M.Holton, R.P.Rambo, I.Rodic, P.J.McGuire, K.Dyer, M.Hammel, G.Meigs, K.A.Frankel, and J.A.Tainer (2013).
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  J Appl Crystallogr, 46, 1.  
21329474 G.Zhao, X.Yin, D.Wu, S.Mao, H.Yin, and B.Zhang (2011).
Clinical features and Cu/Zn superoxide dismutase gene mutations in two Mainland Chinese families with amyotrophic lateral sclerosis.
  Int J Neurosci, 121, 191-195.  
21257910 K.A.Vassall, H.R.Stubbs, H.A.Primmer, M.S.Tong, S.M.Sullivan, R.Sobering, S.Srinivasan, L.A.Briere, S.D.Dunn, W.Colón, and E.M.Meiering (2011).
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20399791 C.Münch, and A.Bertolotti (2010).
Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants.
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21098299 J.R.Auclair, K.J.Boggio, G.A.Petsko, D.Ringe, and J.N.Agar (2010).
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20808835 J.Yin, S.Hu, W.Jiang, L.Liu, S.Lan, X.Song, and C.Liu (2010).
DNA-triggered aggregation of copper, zinc superoxide dismutase in the presence of ascorbate.
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20498711 R.Chia, M.H.Tattum, S.Jones, J.Collinge, E.M.Fisher, and G.S.Jackson (2010).
Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.
  PLoS One, 5, e10627.  
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.
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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).
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  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.
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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.  
19804755 R.S.Williams, G.E.Dodson, O.Limbo, Y.Yamada, J.S.Williams, G.Guenther, S.Classen, J.N.Glover, H.Iwasaki, P.Russell, and J.A.Tainer (2009).
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  Cell, 139, 87-99.
PDB codes: 3hue 3huf
19596823 S.V.Seetharaman, M.Prudencio, C.Karch, S.P.Holloway, D.R.Borchelt, and P.J.Hart (2009).
Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.
  Exp Biol Med (Maywood), 234, 1140-1154.  
19696882 V.Castillo, and S.Ventura (2009).
Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.
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19325915 Z.A.Oztug Durer, J.A.Cohlberg, P.Dinh, S.Padua, K.Ehrenclou, S.Downes, J.K.Tan, Y.Nakano, C.J.Bowman, J.L.Hoskins, C.Kwon, A.Z.Mason, J.A.Rodriguez, P.A.Doucette, B.F.Shaw, and J.Selverstone Valentine (2009).
Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase.
  PLoS ONE, 4, e5004.  
19436494 A.Nordlund, and M.Oliveberg (2008).
SOD1-associated ALS: a promising system for elucidating the origin of protein-misfolding disease.
  HFSP J, 2, 354-364.  
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Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1.
  J Biol Chem, 283, 8340-8350.  
19033195 F.Rousseau, J.Schymkowitz, and M.Oliveberg (2008).
ALS precursor finally shaken into fibrils.
  Proc Natl Acad Sci U S A, 105, 18649-18650.  
19022905 M.Chattopadhyay, A.Durazo, S.H.Sohn, C.D.Strong, E.B.Gralla, J.P.Whitelegge, and J.S.Valentine (2008).
Initiation and elongation in fibrillation of ALS-linked superoxide dismutase.
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18370853 M.Cozzolino, A.Ferri, and M.T.Carrì (2008).
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18666828 Q.Wang, J.L.Johnson, N.Y.Agar, and J.N.Agar (2008).
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PDB code: 2r27
18078545 C.D.Putnam, M.Hammel, G.L.Hura, and J.A.Tainer (2007).
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17592131 L.Banci, I.Bertini, A.Durazo, S.Girotto, E.B.Gralla, M.Martinelli, J.S.Valentine, M.Vieru, and J.P.Whitelegge (2007).
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  Proc Natl Acad Sci U S A, 104, 11263-11267.  
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.
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16785423 D.Summerer, S.Chen, N.Wu, A.Deiters, J.W.Chin, and P.G.Schultz (2006).
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16441516 J.Wang, G.Xu, and D.R.Borchelt (2006).
Mapping superoxide dismutase 1 domains of non-native interaction: roles of intra- and intermolecular disulfide bonding in aggregation.
  J Neurochem, 96, 1277-1288.  
16760466 L.G.Randles, I.Lappalainen, S.B.Fowler, B.Moore, S.J.Hamill, and J.Clarke (2006).
Using model proteins to quantify the effects of pathogenic mutations in Ig-like proteins.
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17146286 P.A.Jonsson, K.S.Graffmo, T.Brännström, P.Nilsson, P.M.Andersen, and S.L.Marklund (2006).
Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1.
  J Neuropathol Exp Neurol, 65, 1126-1136.  
16407238 P.B.Stathopulos, J.A.Rumfeldt, F.Karbassi, C.A.Siddall, J.R.Lepock, and E.M.Meiering (2006).
Calorimetric analysis of thermodynamic stability and aggregation for apo and holo amyotrophic lateral sclerosis-associated Gly-93 mutants of superoxide dismutase.
  J Biol Chem, 281, 6184-6193.  
16516535 P.J.Hart (2006).
Pathogenic superoxide dismutase structure, folding, aggregation and turnover.
  Curr Opin Chem Biol, 10, 131-138.  
17107883 S.D.Khare, M.Caplow, and N.V.Dokholyan (2006).
FALS mutations in Cu, Zn superoxide dismutase destabilize the dimer and increase dimer dissociation propensity: a large-scale thermodynamic analysis.
  Amyloid, 13, 226-235.  
16038997 F.Ding, and N.V.Dokholyan (2005).
Simple but predictive protein models.
  Trends Biotechnol, 23, 450-455.  
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.  
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.  
16152647 S.D.Khare, K.C.Wilcox, P.Gong, and N.V.Dokholyan (2005).
Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation.
  Proteins, 61, 617-632.  
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.  
15034941 B.J.Turner, E.C.Lopes, and S.S.Cheema (2004).
Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts.
  J Cell Biochem, 91, 1074-1084.  
15522970 M.J.Lindberg, J.Normark, A.Holmgren, and M.Oliveberg (2004).
Folding of human superoxide dismutase: disulfide reduction prevents dimerization and produces marginally stable monomers.
  Proc Natl Acad Sci U S A, 101, 15893-15898.  
15501681 N.J.Marianayagam, M.Sunde, and J.M.Matthews (2004).
The power of two: protein dimerization in biology.
  Trends Biochem Sci, 29, 618-625.  
15475574 S.D.Khare, M.Caplow, and N.V.Dokholyan (2004).
The rate and equilibrium constants for a multistep reaction sequence for the aggregation of superoxide dismutase in amyotrophic lateral sclerosis.
  Proc Natl Acad Sci U S A, 101, 15094-15099.  
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.  
14675544 M.E.Huff, W.E.Balch, and J.W.Kelly (2003).
Pathological and functional amyloid formation orchestrated by the secretory pathway.
  Curr Opin Struct Biol, 13, 674-682.  
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.