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Navigating the ClpB channel to solution

Nature Structural & Molecular Biology volume 12, pages 4–6 (2005)Cite this article

New work places the Hsp70/DnaK system in an opening role in protein disaggregation, facilitating the extraction of individual polypeptides from the aggregate surface to the axial channel of Hsp104/ClpB. It also reinforces a long-standing belief that reactivation rather than simple clearance of aggregated protein is necessary for cell stress tolerance.

Excessive protein misfolding and aggregation can be fatal, and contribute to devastating disorders as diverse as sickle cell anemia, type II diabetes and new variant Creutzfeldt-Jakob disease1. However, to function optimally, cells must maintain a highly crowded macromolecular interior (up to 400 mg ml−1), which accentuates the risk of protein aggregation2. Thus, sophisticated molecular chaperone, osmolyte and proteolytic systems have evolved to minimize protein misfolding and eliminate misfolded conformers when they appear1,2. Environmental stress, such as high temperatures, can overwhelm these systems and induce potentially catastrophic protein aggregation. In fungi, the survival of such insults is increased up to 10,000-fold by Hsp104 (refs. 3,4), a member the Hsp100/Clp subfamily of AAA+ (ATPases associated with diverse activities) proteins. The Hsp104 homologs ClpB and Hsp101 are equally critical in stress tolerance in bacteria5 and plants6. Hsp104/ClpB collaborate with the Hsp70/DnaK system to dissolve and reactivate aggregated proteins4,7,8. Protein aggregates are notoriously irksome to study and precisely how their dissolution is achieved remains unclear. Elegant studies by Mogk and colleagues9 now illuminate several mechanistic aspects of ClpB-mediated disaggregation and its consequences for cell viability after heat shock.

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Figure 1: The architecture of the ClpB hexamer.
Figure 2: Modes of Hsp104/ClpB-mediated disaggregation.

References

  1. Dobson, C.M. Nature 426, 884–890 (2003).

    Article  CAS  Google Scholar 

  2. Ellis, R.J. Trends Biochem. Sci. 26, 597–604 (2001).

    Article  CAS  Google Scholar 

  3. Sanchez, Y. & Lindquist, S.L. Science 248, 1112–1115 (1990).

    Article  CAS  Google Scholar 

  4. Parsell, D.A., Kowal, A.S., Singer, M.A. & Lindquist, S. Nature 372, 475–478 (1994).

    Article  CAS  Google Scholar 

  5. Mogk, A. et al. EMBO J. 18, 6934–6949 (1999).

    Article  CAS  Google Scholar 

  6. Queitsch, C., Hong, S.W., Vierling, E. & Lindquist, S. Plant Cell 12, 479–492 (2000).

    Article  CAS  Google Scholar 

  7. Glover, J.R. & Lindquist, S. Cell 94, 73–82 (1998).

    Article  CAS  Google Scholar 

  8. Goloubinoff, P., Mogk, A., Zvi, A.P., Tomoyasu, T. & Bukau, B. Proc. Natl. Acad. Sci. USA 96, 13732–13737 (1999).

    Article  CAS  Google Scholar 

  9. Weibezahn, J. et al. Cell 119, 653–665 (2004).

    Article  CAS  Google Scholar 

  10. Sauer, R.T. et al. Cell 119, 9–18 (2004).

    Article  CAS  Google Scholar 

  11. Lee, S. et al. Cell 115, 229–240 (2003).

    Article  CAS  Google Scholar 

  12. Hattendorf, D.A. & Lindquist, S.L. EMBO J. 21, 12–21 (2002).

    Article  CAS  Google Scholar 

  13. Cashikar, A.G. et al. Mol. Cell 9, 751–760 (2002).

    Article  CAS  Google Scholar 

  14. Zietkiewicz, S., Krzewska, J. & Liberek, K. J. Biol. Chem. 279, 44376–44383 (2004).

    Article  CAS  Google Scholar 

  15. Weibezahn, J., Schlieker, C., Bukau, B. & Mogk, A. J. Biol. Chem. 278, 32608–32617 (2003).

    Article  CAS  Google Scholar 

  16. Schlee, S., Beinker, P., Akhrymuk, A. & Reinstein, J. J. Mol. Biol. 336, 275–285 (2004).

    Article  CAS  Google Scholar 

  17. Schlieker, C. et al. Nat. Struct. Mol. Biol. 11, 607–615 (2004).

    Article  CAS  Google Scholar 

  18. Wang, J. et al. Structure 9, 177–184 (2001).

    Article  CAS  Google Scholar 

  19. Lum, R., Tkach, J.M., Vierling, E. & Glover, J.R. J. Biol. Chem. 279, 29139–29146 (2004).

    Article  CAS  Google Scholar 

  20. Joshi, S.A., Hersch, G.L., Baker, T.A. & Sauer, R.T. Nat. Struct. Mol. Biol. 11, 404–411 (2004).

    Article  CAS  Google Scholar 

  21. Schirmer, E.C., Homann, O.R., Kowal, A.S. & Lindquist, S. Mol. Biol. Cell 15, 2061–2072 (2004).

    Article  CAS  Google Scholar 

  22. Mogk, A. et al. J. Biol. Chem. 278, 17615–17624 (2003).

    Article  CAS  Google Scholar 

  23. Dougan, D.A., Reid, B.G., Horwich, A.L. & Bukau, B. Mol. Cell 9, 673–683 (2002).

    Article  CAS  Google Scholar 

  24. Shorter, J. & Lindquist, S. Science 304, 1793–1797 (2004).

    Article  CAS  Google Scholar 

  25. Friant, S., Meier, K.D. & Riezman, H. EMBO J. 22, 3783–3791 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Cashikar and G. Kramer for comments on the manuscript.

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  1. Whitehead Institute of Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    James Shorter & Susan Lindquist

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Shorter, J., Lindquist, S. Navigating the ClpB channel to solution. Nat Struct Mol Biol 12, 4–6 (2005). https://doi.org/10.1038/nsmb0105-4

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