Skip to main content
SpringerLink
Log in

Dynamics-Function Relationships of the Small Heat-Shock Proteins

  • Chapter
The Big Book on Small Heat Shock Proteins

Part of the book series: Heat Shock Proteins ((HESP,volume 8))

Abstract

The Small Heat-Shock Proteins (sHSPs) are a widespread family of molecular chaperones that tend to populate ensembles of inter-converting conformational and oligomeric states at equilibrium. How this dynamic structure is linked to the sHSPs’ ability to rapidly bind and sequester target proteins, intercepting them en route to aggregation and deposition during disease and cellular stress, is a controversial topic. Partly this is because the dynamics of the sHSPs pose challenges to all biophysical and structural biology techniques, rendering them difficult to study. Here we give a personal view on recent insights that have been obtained on the dynamic motions these proteins undergo, their regulation in the cell, and hypothesise on how they may directly underpin sHSP activity.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aquilina JA, Benesch JLP, Ding LL, Yaron O, Horwitz J, Robinson CV (2004) Phosphorylation of alphaB-crystallin alters chaperone function through loss of dimeric substructure. J Biol Chem 279:28675–28680

    Article  CAS  PubMed  Google Scholar 

  • Aquilina JA, Shrestha S, Morris AM, Ecroyd H (2013) Structural and functional aspects of hetero-oligomers formed by the small heat shock proteins alphaB-crystallin and HSP27. J Biol Chem 288:13602–13609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bagnéris C, Bateman OA, Naylor CE, Cronin N, Boelens WC, Keep NH, Slingsby C (2009) Crystal structures of α-crystallin domain dimers of αB-crystallin and Hsp20. J Mol Biol 392:1242–1252

    Article  PubMed  Google Scholar 

  • Baldwin AJ, Hilton GR, Lioe H, Bagneris C, Benesch JLP, Kay LE (2011a) Quaternary dynamics of aB-crystallin as a direct consequence of localised tertiary fluctuations in the C-terminus. J Mol Biol 413:310–320

    Article  CAS  PubMed  Google Scholar 

  • Baldwin AJ, Lioe H, Hilton GR, Kay LE, Benesch JLP (2011b) The polydispersity of αB-crystallin is rationalised by an inter-converting polyhedral architecture. Structure 19:1855–1863

    Article  CAS  PubMed  Google Scholar 

  • Baldwin AJ, Lioe H, Robinson CV, Kay LE, Benesch JLP (2011c) αB-crystallin polydispersity is a consequence of unbiased quaternary dynamics. J Mol Biol 413:297–309

    Article  CAS  PubMed  Google Scholar 

  • Basha E, O’Neill H, Vierling E (2011) Small heat shock proteins and alpha-crystallins: dynamic proteins with flexible functions. Trends Biochem Sci 37(3):106–117

    Google Scholar 

  • Benesch JLP, Ruotolo BT (2011) Mass spectrometry: an approach come-of-age for structural and dynamical biology. Curr Opin Struct Biol 21:641–649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Benesch JLP, Aquilina JA, Baldwin AJ, Rekas A, Stengel F, Lindner RA, Basha E, Devlin GL, Horwitz J, Vierling E et al (2010) The quaternary organization and dynamics of the molecular chaperone HSP26 are thermally regulated. Chem Biol 17:1008–1017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Binger KJ, Ecroyd H, Yang S, Carver JA, Howlett GJ, Griffin MD (2013) Avoiding the oligomeric state: alphaB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils. FASEB J 27:1214–1222

    Article  CAS  PubMed  Google Scholar 

  • Bloemendal H, de Jong W, Jaenicke R, Lubsen NH, Slingsby C, Tardieu A (2004) Ageing and vision: structure, stability and function of lens crystallins. Prog Biophys Mol Biol 86:407–485

    Article  CAS  PubMed  Google Scholar 

  • Bova MP, Yaron O, Huang QL, Ding LL, Haley DA, Stewart PL, Horwitz J (1999) Mutation R120G in alpha B-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function. Proc Natl Acad Sci U S A 96:6137–6142

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Braun N, Zacharias M, Peschek J, Kastenmuller A, Zou J, Hanzlik M, Haslbeck M, Rappsilber J, Buchner J, Weinkauf S (2011) Multiple molecular architectures of the eye lens chaperone alphaB-crystallin elucidated by a triple hybrid approach. Proc Natl Acad Sci U S A 108:20491–20496

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Campbell ID (2002) Timeline: the march of structural biology. Nat Rev Mol Cell Biol 3:377–381

    Article  CAS  PubMed  Google Scholar 

  • Cheng GL, Basha E, Wysocki VH, Vierling E (2008) Insights into small heat shock protein and substrate structure during chaperone action derived from hydrogen/deuterium exchange and mass spectrometry. J Biol Chem 283:26634–26642

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Clark AR, Naylor CE, Bagneris C, Keep NH, Slingsby C (2011) Crystal structure of R120G disease mutant of human alphaB-crystallin domain dimer shows closure of a groove. J Mol Biol 408:118–134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Delbecq SP, Klevit RE (2013) One size does not fit all: the oligomeric states of alphaB crystallin. FEBS Lett 587:1073–1080

    Article  CAS  PubMed  Google Scholar 

  • Delbecq S, Jehle S, Klevit R (2012) Binding determinants of the small heat shock protein, [alpha]B-crystallin: recognition of the ‘IxI’ motif. EMBO J 31:4587–4594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • den Engelsman J, Boros S, Dankers PY, Kamps B, Vree Egberts WT, Bode CS, Lane LA, Aquilina JA, Benesch JLP, Robinson CV et al (2009) The small heat-shock proteins HSPB2 and HSPB3 form well-defined heterooligomers in a unique 3 to 1 subunit ratio. J Mol Biol 393:1022–1032

    Article  Google Scholar 

  • Franzmann TM, Menhorn P, Walter S, Buchner J (2008) Activation of the chaperone Hsp26 is controlled by the rearrangement of its thermosensor domain. Mol Cell 29:207–216

    Article  CAS  PubMed  Google Scholar 

  • Friedrich KL, Giese KC, Buan NR, Vierling E (2004) Interactions between small heat shock protein subunits and substrate in small heat shock protein-substrate complexes. J Biol Chem 279:1080–1089

    Article  CAS  PubMed  Google Scholar 

  • Gould SJ, Lewontin RC (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc R Soc Lond B Biol Sci 205:581–598

    Article  CAS  PubMed  Google Scholar 

  • Hanazono Y, Takeda K, Oka T, Abe T, Tomonari T, Akiyama N, Aikawa Y, Yohda M, Miki K (2013) Nonequivalence observed for the 16-meric structure of a small heat shock protein, SpHsp16.0, from Schizosaccharomyces pombe. Structure 21:220–228

    Article  CAS  PubMed  Google Scholar 

  • Hayes D, Napoli V, Mazurkie A, Stafford WF, Graceffa P (2009) Phosphorylation dependence of hsp27 multimeric size and molecular chaperone function. J Biol Chem 284:18801–18807

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hilton GR, Hochberg GKA, Laganowsky A, McGinnigle SI, Baldwin AJ, Benesch JLP (2013a) C-terminal interactions mediate the quaternary dynamics of αB-crystallin. Philos Trans R Soc Lond B Biol Sci 368:20110405

    Google Scholar 

  • Hilton GR, Lioe H, Stengel F, Baldwin AJ, Benesch JLP (2013b) Small heat-shock proteins: paramedics of the cell. Top Curr Chem 328:69–98

    CAS  PubMed  Google Scholar 

  • Hochberg GKA, Benesch JLP (2014) Dynamical structure of alphaB-crystallin. Prog Biophys Mol Biol 115:11–20

    Article  CAS  PubMed  Google Scholar 

  • Hochberg GKA, Ecroyd H, Liu C, Cox D, Cascio D, Sawaya MR, Collier MP, Stroud J, Carver JA, Baldwin AJ et al (2014) The structured core domain of alphaB-crystallin can prevent amyloid fibrillation and associated toxicity. Proc Natl Acad Sci U S A 111:E1562–E1570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jehle S, van Rossum B, Stout JR, Noguchi SM, Falber K, Rehbein K, Oschkinat H, Klevit RE, Rajagopal P (2009) alphaB-crystallin: a hybrid solid-state/solution-state NMR investigation reveals structural aspects of the heterogeneous oligomer. J Mol Biol 385:1481–1497

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jehle S, Rajagopal P, Bardiaux B, Markovic S, Kuhne R, Stout JR, Higman VA, Klevit RE, van Rossum BJ, Oschkinat H (2010) Solid-state NMR and SAXS studies provide a structural basis for the activation of alphaB-crystallin oligomers. Nat Struct Mol Biol 17:1037–1042

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Karplus M, McCammon JA (1983) Dynamics of proteins: elements and function. Annu Rev Biochem 52:263–300

    Article  CAS  PubMed  Google Scholar 

  • Knowles TP, Shu W, Devlin GL, Meehan S, Auer S, Dobson CM, Welland ME (2007) Kinetics and thermodynamics of amyloid formation from direct measurements of fluctuations in fibril mass. Proc Natl Acad Sci U S A 104:10016–10021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koteiche HA, Berengian AR, McHaourab HS (1998) Identification of protein folding patterns using site-directed spin labeling. Structural characterization of a beta-sheet and putative substrate binding regions in the conserved domain of alpha A-crystallin. Biochemistry 37:12681–12688

    Article  CAS  PubMed  Google Scholar 

  • Kriehuber T, Rattei T, Weinmaier T, Bepperling A, Haslbeck M, Buchner J (2010) Independent evolution of the core domain and its flanking sequences in small heat shock proteins. FASEB J 24:3633–3642

    Article  CAS  PubMed  Google Scholar 

  • Laganowsky A, Benesch JLP, Landau M, Ding L, Sawaya M, Cascio D, Huang Q, Robinson CV, Horwitz J, Eisenberg D (2010) Crystal structures of truncated alphaA and alphaB crystallins reveal structural mechanisms of polydispersity important for eye lens function. Protein Sci 19:1031–1043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McDonald ET, Bortolus M, Koteiche HA, McHaourab HS (2012) Sequence, structure, and dynamic determinants of Hsp27 (HspB1) equilibrium dissociation are encoded by the N-terminal domain. Biochemistry 51:1257–1268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McHaourab HS, Godar JA, Stewart PL (2009) Structure and mechanism of protein stability sensors: chaperone activity of small heat shock proteins. Biochemistry 48:3828–3837

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michiel M, Skouri-Panet F, Duprat E, Simon S, Ferard C, Tardieu A, Finet S (2009) Abnormal assemblies and subunit exchange of alpha B-crystallin R120 mutants could be associated with destabilization of the dimeric substructure. Biochemistry 48:442–453

    Article  CAS  PubMed  Google Scholar 

  • Mymrikov EV, Seit-Nebi AS, Gusev NB (2012) Heterooligomeric complexes of human small heat shock proteins. Cell Stress Chaperones 17:157–169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Painter AJ, Jaya N, Basha E, Vierling E, Robinson CV, Benesch JLP (2008) Real-time monitoring of protein complexes reveals their quaternary organization and dynamics. Chem Biol 15:246–253

    Article  CAS  PubMed  Google Scholar 

  • Papoian GA (2008) Proteins with weakly funneled energy landscapes challenge the classical structure-function paradigm. Proc Natl Acad Sci U S A 105:14237–14238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patel S, Vierling E, Tama F (2014) Replica exchange molecular dynamics simulations provide insight into substrate recognition by small heat shock proteins. Biophys J 106:2644–2655

    Article  CAS  PubMed  Google Scholar 

  • Peschek J, Braun N, Rohrberg J, Back K, Kriehuber T, Kastenmüller A, Weinkauf S, Buchner J (2013) Regulated structural transitions unleash the chaperone activity of αB-crystallin. Proc Natl Acad Sci U S A 110(40):E3780–E3789, 201308898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Poulain P, Gelly JC, Flatters D (2010) Detection and architecture of small heat shock protein monomers. PLoS ONE 5:e9990

    Article  PubMed Central  PubMed  Google Scholar 

  • Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991

    Article  CAS  PubMed  Google Scholar 

  • Richter K, Haslbeck M, Buchner J (2010) The heat shock response: life on the verge of death. Mol Cell 40:253–266

    Article  CAS  PubMed  Google Scholar 

  • Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J et al (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress tumor necrosis factor alpha by phosphorylation. J Biol Chem 274:18947–18956

    Article  CAS  PubMed  Google Scholar 

  • Shashidharamurthy R, Koteiche HA, Dong J, McHaourab HS (2005) Mechanism of chaperone function in small heat shock proteins: dissociation of the HSP27 oligomer is required for recognition and binding of destabilized T4 lysozyme. J Biol Chem 280:5281–5289

    Article  CAS  PubMed  Google Scholar 

  • Sobott F, Benesch JLP, Vierling E, Robinson CV (2002) Subunit exchange of multimeric protein complexes. Real-time monitoring of subunit exchange between small heat shock proteins by using electrospray mass spectrometry. J Biol Chem 277:38921–38929

    Article  CAS  PubMed  Google Scholar 

  • Stengel F, Baldwin AJ, Painter AJ, Jaya N, Basha E, Kay LE, Vierling E, Robinson CV, Benesch JLP (2010) Quaternary dynamics and plasticity underlie small heat shock protein chaperone function. Proc Natl Acad Sci U S A 107:2007–2012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stengel F, Baldwin AJ, Bush MF, Hilton GR, Lioe H, Basha E, Jaya N, Vierling E, Benesch JLP (2012) Dissecting heterogeneous molecular chaperone complexes using a mass spectrum deconvolution approach. Chem Biol 19:599–607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • van Montfort RL, Basha E, Friedrich KL, Slingsby C, Vierling E (2001) Crystal structure and assembly of a eukaryotic small heat shock protein. Nat Struct Biol 8:1025–1030

    Article  PubMed  Google Scholar 

  • Weeks SD, Baranova EV, Heirbaut M, Beelen S, Shkumatov AV, Gusev NB, Strelkov SV (2014) Molecular structure and dynamics of the dimeric human small heat shock protein HSPB6. J Struct Biol 185:342–354

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

JLPB would like to thank all members of his group, past and present, for their enthusiasm, hard work, and intellectual insights that have driven our research programme in the study of this fascinating family of proteins. Similarly, we are extremely grateful to our collaborators, many of which have also contributed chapters to this book, who continue to galvanise our work, and make this field such an exciting and stimulating one to work in. GKAH is funded by the Doctoral Training Centre in System Biology that is funded by the Engineering and Physical Sciences Research Council, and JLPB by the Royal Society.

Author information

Authors and Affiliations

  1. Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, OX1 3QZ, UK

    Georg K. A. Hochberg & Justin L. P. Benesch

Authors
  1. Georg K. A. Hochberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justin L. P. Benesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Justin L. P. Benesch .

Editor information

Editors and Affiliations

  1. Department of Molecular Biology, Medical Biochemistry & Pathology Medical School Lab Cell & Developmental Genetics IBIS, Université Laval, Quebec, Québec, Canada

    Robert M. Tanguay

  2. Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, USA

    Lawrence E. Hightower

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hochberg, G.K.A., Benesch, J.L.P. (2015). Dynamics-Function Relationships of the Small Heat-Shock Proteins. In: Tanguay, R., Hightower, L. (eds) The Big Book on Small Heat Shock Proteins. Heat Shock Proteins, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-16077-1_3

Download citation

Publish with us

Policies and ethics

Search

Navigation