Skip to main content
SpringerLink
Log in

An in silico study of the effect of SOD1 electrostatic loop dynamics on amyloid‑like filament formation

  • Biophysics Letter
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

Superoxide dismutase [Cu–Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxides. A wide range of SOD1 variants are linked to inherited, or familial, amyotrophic lateral sclerosis, a progressive and fatal neurodegenerative disease. Aberrant SOD1 oligomerization has been strongly implicated in disease causation, even for sporadic ALS, or SALS, which accounts for ~90 % of ALS cases. Small heat shock proteins (sHSP) have been shown to protect against amyloid fibril formation in vitro, and the sHSP αB-crystallin suppresses in vitro aggregation of SOD1. We are seeking to elucidate the structural features of both SOD1 amyloid formation and αB-crystallin amyloid suppression. Specifically, we have used a flexible docking protocol to refine our model of a SOD1 non-obligate tetramer, postulated to function as a transient desolvating complex. Homology modeling and molecular dynamics (MD) are used to supply the missing structural elements of a previously characterized SOD1 amyloid filament, thereby providing a structural analysis for the observed gain of interaction. This completed filament is then further modified using MD to provide a structural model for protofibril capping of SOD1 filaments by αB-crystallin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • Antonyuk S, Elam JS, Hough MA, Strange RW, Doucette PA, Rodriguez JA, Hayward LJ, Valentine JS, Hart PJ, Hasnain SS (2005) Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg. Protein Sci 14:1201–1213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bershtein S, Mu W, Shakhnovich EI (2012) Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations. Proc Natl Acad Sci USA 109:4857–4862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bilen J, Bonini NM (2007) Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3:1950–1964

    Article  CAS  PubMed  Google Scholar 

  • Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217

    Article  CAS  Google Scholar 

  • Caughey B, Lansbury PT Jr (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders*. Annu Rev Neurosci 26:267–298

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Li L, Weng Z (2003) ZDOCK: an initial-stage protein-docking algorithm. Proteins 52:80–87

    Article  CAS  PubMed  Google Scholar 

  • Chiti F, Dobson CM (2009) Amyloid formation by globular proteins under native conditions. Nat Chem Biol 5:15–22

    Article  CAS  PubMed  Google Scholar 

  • Claxton DP, Zou P, Mchaourab HS (2008) Structure and orientation of T4 lysozyme bound to the small heat shock protein α-crystallin. J Mol Biol 375:1026–1039

    Article  CAS  PubMed  Google Scholar 

  • Ecroyd H, Carver JA (2009) Crystallin proteins and amyloid fibrils. Cell Mol Life Sci 66:62–81

    Article  CAS  PubMed  Google Scholar 

  • Elam JS, Taylor AB, Strange R, Antonyuk S, Doucette PA, Rodriguez J, Hart PJ (2003) Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS. Nat Struct Mol Biol 10:461–467

    Article  CAS  Google Scholar 

  • Fernández A, Ridgway S (2003) Dehydron: a structure-encoded signal for protein interactions. Biophys J 85:1914–1928

    Article  PubMed  PubMed Central  Google Scholar 

  • Fernández A, Scheraga H (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113–118

    Article  CAS  PubMed  Google Scholar 

  • Grad LI, Guest WC, Yanai A, Pokrishevsky E, O’Neill MA, Gibbs E, Cashman NR (2011) Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci 108:16398–16403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, Cashman NA (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and-independent mechanisms. Proc Natl Acad Sci 111:3620–3625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu L, Abulimiti A, Li W, Chang ZJ, J Mol Biol 319 (2002) 517–526

  • Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184

    Article  CAS  PubMed  Google Scholar 

  • Hart PJ, Liu H, Pellegrini M, Nersissian AM, Gralla EB, Valentine JS, Eisenberg D (1998) Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis. Protein Sci 7:545–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Healy EF (2011) The effect of desolvation on nucleophilic halogenase activity. Comput Theor Chem 964:91–93

    Article  CAS  Google Scholar 

  • Healy EF (2012) A model for heterooligomer formation in the heat shock response of Escherichia coli. Biochem Biophys Res Commun 420:639–643

    Article  CAS  PubMed  Google Scholar 

  • Healy EF (2015) A model for non-obligate oligomer formation in protein aggregation. Biochem Biophys Res Commun 465:523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Healy EF, King PJ (2012) A mechanism of action for small heat shock proteins. Biochem Biophys Res Commun 417:268–273

    Article  CAS  PubMed  Google Scholar 

  • Healy EF, Johnson S, Hauser C, King P (2009) Tyrosine kinase inhibition: ligand binding and conformational change in c-Kit and c-Abl. FEBS Lett 583:2899–2906

    Article  CAS  PubMed  Google Scholar 

  • Healy EF, Little C, King PJ (2014) A model for small heat shock protein inhibition of polyglutamine aggregation. Cell Biochem Biophys 69:275–281

    Article  CAS  PubMed  Google Scholar 

  • Hochberg GK, Ecroyd H, Liu C, Cox D, Cascio D, Sawaya MR, Laganowsky A (2014) The structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity. Proc Natl Acad Sci 111:E1562–E1570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horwitz J (2003) Alpha-crystallin. Exp Eye Res 76:145–153

    Article  CAS  PubMed  Google Scholar 

  • Kato S, Hayashi H, Nakashima K, Nanba E, Kato M, Hirano A, Nakano I, Asayama K, Ohama E (1997) Pathological characterization of astrocytic hyaline inclusions in familial amyotrophic lateral sclerosis. Am J Pathol 151:611

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kelly JW (1998) The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr Opin Struct Biol 8:101–106

    Article  CAS  PubMed  Google Scholar 

  • Khare SD, Dokholyan NV (2006) Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants. Proc Natl Acad Sci USA 103:3147–3152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirkitadze MD, Bitan G, Teplow DB (2002) Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res 69:567–577

    Article  CAS  PubMed  Google Scholar 

  • Klein WL, Krafft GA, Finch CE (2001) Targeting small Aβ oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24:219–224

    Article  CAS  PubMed  Google Scholar 

  • Kulig M, Ecroyd H (2012) The small heat-shock protein αB-crystallin uses different mechanisms of chaperone action to prevent the amorphous versus fibrillar aggregation of α-lactalbumin. Biochem J 448:343–352

    Article  CAS  PubMed  Google Scholar 

  • Levy ED, Boeri EE, Robinson CV, Teichmann SA (2008) Assembly reflects evolution of protein complexes. Nature 453:1262–1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mainz A, Peschek J, Stavropoulou M, Back KC, Bardiaux B, Asami S, Prade E, Peters C, Weinkauf S, Buchner J, Reif B (2015) The chaperone [alpha] B-crystallin uses different interfaces to capture an amorphous and an amyloid client. Nat Struct Mol Biol 22:898–905

    CAS  PubMed  Google Scholar 

  • Marsh JA, Teichmann SA (2014) Protein flexibility facilitates quaternary structure assembly and evolution. PLoS Biol 12:e1001870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moal IH, Bates PA (2010) SwarmDock and the use of normal modes in protein-protein docking. Int J Mol Sci 11:3623–3648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molnar KS, Murat N, Karabacak NM, Johnson JL, Wang Q, Tiwari A, Hayward LJ, Coales SJ, Hamuro Y, Agar JN (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redler RL, Fee L, Fay JM, Caplow M, Dokholyan NV (2014) Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS). Biochemistry 53:2423–2432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robertson AL, Headeyb SJ, Saunders HM, Ecroyd H, Scanlon HM, Carver JA, Bottomley SP (2010) Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation. Proc Natl Acad Sci USA 107:10424–10429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekhar A, Rumfeldt JA, Broom HR, Doyle CM, Bouvignies G, Meiering EM, Kay LE (2015) Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways. Elife 4:e07296

    Article  PubMed  PubMed Central  Google Scholar 

  • Strange RW, Antonyuk SV, Hough MA, Doucette PA, Valentine JS, Hasnain SS (2006) Variable metallation of human superoxide dismutase: atomic resolution crystal structures of Cu–Zn, Zn–Zn and as-isolated wild-type enzymes. J Mol Biol 356:1152–1162

    Article  CAS  PubMed  Google Scholar 

  • Torchala M, Moal IH, Chaleil RAG, Fernandez-Recio J, Bates PA (2013) SwarmDock: a server for flexible protein-protein docking. Bioinformatics 29:807–809

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Johnson JL, Agar NY, Agar JN (2008) Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol 6:e170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yerbury JJ, Gower D, Vanags L, Roberts K, Lee JA, Ecroyd H (2013) The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro. Cell Stress Chaperones 18:251–257

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge the support of the National Institute of General Medical Services (1K12GM102745), as well as Welch Foundation (Grant# BH-0018) for its continuing support of the Chemistry Department at St. Edward’s University.

Author information

Authors and Affiliations

  1. Department of Chemistry, St. Edward’s University, Austin, TX, 78704, USA

    Eamonn F. Healy & Luis Cervantes

Authors
  1. Eamonn F. Healy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis Cervantes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eamonn F. Healy.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Healy, E.F., Cervantes, L. An in silico study of the effect of SOD1 electrostatic loop dynamics on amyloid‑like filament formation. Eur Biophys J 45, 853–859 (2016). https://doi.org/10.1007/s00249-016-1163-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-016-1163-9

Keywords

Search

Navigation