Commentary | Published:

Protein folding in the cell: an inside story

Nature Medicine volume 17, pages 12111216 (2011) | Download Citation

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Principles that govern the folding of protein chains. Science 181, 223–230 (1973).

  2. 2.

    et al. Structure and expression of a cDNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase. Science 224, 1068–1074 (1984).

  3. 3.

    , , & Import and processing of human ornithine transcarbamylase precursor by mitochondria from Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 84, 4063–4067 (1987).

  4. 4.

    Speculations on the functions of the major heat-shock and glucose-regulated proteins. Cell 46, 959–961 (1986).

  5. 5.

    et al. Uncoating ATPase is a member of the 70 kilodalton family of stress proteins. Cell 45, 3–13 (1986).

  6. 6.

    & Binding of a specific ligand inhibits import of a purified precursor protein into mitochondria. Nature 322, 228–232 (1986).

  7. 7.

    et al. Mitochondrial heat shock protein HSP60 is essential for assembly of proteins imported into yeast mitochondria. Nature 337, 620–625 (1989).

  8. 8.

    , , & Protein folding in mitochondria requires complex formation with HSP60 and ATP hydrolysis. Nature 341, 125–130 (1989).

  9. 9.

    & A highly evolutionarily conserved mitochondrial protein is structurally related to the protein encoded by the Escherichia coli groEL gene. Mol. Cell. Biol. 8, 371–380 (1988).

  10. 10.

    , & Characterization of the yeast HSP60 gene coding for a mitochondrial assembly factor. Nature 337, 655–659 (1989).

  11. 11.

    , , , & Identification of in vivo substrates of the yeast mitochondrial chaperonins reveals overlapping but non-identical requirement for hsp60 and hsp10. EMBO J. 17, 5868–5876 (1998).

  12. 12.

    , , & Role of the host cell in bacteriophage morphogenesis: Effects of a bacterial mutation on T4 head assembly. Nat. New Biol. 239, 38–41 (1972).

  13. 13.

    & Involvement of a bacterial factor in morphogenesis of bacteriophage capsid. Nat. New Biol. 239, 34–37 (1972).

  14. 14.

    & Protein synthesis in chloroplasts. IX. Assembly of newly-synthesized large subunits into ribulose bisphosphate carboxylase in isolated intact pea chloroplasts. Biochim. Biophys. Acta 608, 19–31 (1980).

  15. 15.

    et al. Homologous plant and bacterial proteins chaperone oligomeric protein assembly. Nature 333, 330–334 (1988).

  16. 16.

    et al. A molecular chaperone from a thermophilic archaebacterium is related to the eukaryotic protein t-complex polypeptide-1. Nature 354, 490–493 (1991).

  17. 17.

    & The yeast homolog to mouse Tcp-1 affects microtubule-mediated processes. Mol. Cell. Biol. 11, 2629–2640 (1991).

  18. 18.

    , , , & T-complex polypeptide-1 is a subunit of a heteromeric particle in the eukaryotic cytosol. Nature 358, 249–252 (1992).

  19. 19.

    et al. TCP1 complex is a molecular chaperone in tubulin biogenesis. Nature 358, 245–248 (1992).

  20. 20.

    , , , & A cytoplasmic chaperonin that catalyzes b-actin folding. Cell 69, 1043–1050 (1992).

  21. 21.

    , , & Reconstitution of active dimeric ribulose bisphosphate carboxylase from an unfolded state depends on two chaperonin proteins and MgATP. Nature 342, 884–889 (1989).

  22. 22.

    et al. Chaperonin-mediated protein folding occurs at the surface of GroEL via a molten globule-like intermediate. Nature 352, 36–42 (1991).

  23. 23.

    , , , & Chaperonin-mediated protein folding: GroES binds to one end of the GroEL cylinder, which accommodates the protein substrate within its central cavity. EMBO J. 11, 4757–4765 (1992).

  24. 24.

    , , , & A polypeptide bound to the chaperonin GroEL is localized within a central cavity. Proc. Natl. Acad. Sci. USA 90, 3978–3982 (1993).

  25. 25.

    et al. Crystal structure of GroEL at 2.8 Å. Nature 371, 578–586 (1994).

  26. 26.

    , , , & The 2.4 Å crystal structure of the bacterial chaperonin GroEL complexed with ATP gamma S. Nat. Struct. Biol. 3, 170–177 (1986).

  27. 27.

    et al. ATP induces large quaternary rearrangements in a cage-like chaperonin structure. Curr. Biol. 3, 265–273 (1993).

  28. 28.

    , , & Residues in chaperonin GroEL required for polypeptide binding and release. Nature 371, 614–619 (1994).

  29. 29.

    , , & Binding of chaperonins. Nature 353, 25–26 (1991).

  30. 30.

    et al. Mechanism of GroEL action: Productive release of polypeptide from a sequestered position under GroES. Cell 83, 577–587 (1995).

  31. 31.

    , , , & Characterization of the active intermediate of a GroEL-GroES-mediated protein folding reaction. Cell 84, 481–490 (1996).

  32. 32.

    , , & GroEL-mediated protein folding proceeds by multiple rounds of release and rebinding of non-native forms. Cell 78, 693–702 (1994).

  33. 33.

    , , , & The chaperonin ATPase cycle: mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell 87, 241–251 (1996).

  34. 34.

    , & The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex. Nature 388, 741–750 (1997).

  35. 35.

    et al. Cytochromes c1 and b2 are sorted to the intermembrane space of yeast miotchondria by a stop-transfer mechanism. Cell 69, 809–822 (1992).

  36. 36.

    , & GroEL-GroES-mediated protein folding. Chem. Rev. 106, 1917–1930 (2006).

  37. 37.

    & Nested cooperativity in the ATPase activity in the oligomeric chaperonin GroEL. Biochemistry 34, 5303–5308 (1995).

  38. 38.

    , & The origins and consequences of asymmetry in the chaperonin reaction cycle. J. Mol. Biol. 249, 138–152 (1995).

  39. 39.

    et al. Distinct actions of cis and trans ATP within the double ring of the chaperonin GroEL. Nature 388, 792–798 (1997).

  40. 40.

    et al. GroEL-GroES cycling: ATP and non-native polypeptide direct alternation of folding-active rings. Cell 97, 325–338 (1999).

  41. 41.

    & The GroEL/GroES chaperonin machine. in Molecular Machines in Biology (ed. Frank, J.) (Cambridge Univ. Press, in press).

Download references

Acknowledgements

Many of the major participants in the chaperonin work referred to above are pictured in the illustration on p. xiii. There have been many other collaborators, both in the early work and more recently, who also contributed substantially to the understanding of this system. I regret that space limitations prevented me from referring to them here, but I want to express how deeply grateful I am to everyone with whom I've interacted. Surely, the recognition of this work is shared by all of us. But, more selfishly, it has been a pure joy for me over these past 20 years to work in the lab, at the bench, day by day and side by side with my group members, sharing our ideas, dreams, reagents, frustrations and, of course, joys of discovery as a scientific family. No one could ask for a more enjoyable life. I wish to thank the US National Institutes of Health for supporting the early phase of our work and the Howard Hughes Medical Institute (HHMI) for supporting our subsequent work. I am particularly grateful to the HHMI for allowing me to 'follow my nose' through this work, no matter how risky the undertaking. I also thank HHMI for making our work environment a paradise in which to pursue ideas and do experiments. Finally, I thank W. Fenton for his critical comments during the preparation of this manuscript.

Author information

Affiliations

  1. Arthur L. Horwich is at the Yale University School of Medicine, New Haven, Connecticut, USA.

    • Arthur L Horwich

Authors

  1. Search for Arthur L Horwich in:

Competing interests

The author declares no competing financial interests.

Corresponding author

Correspondence to Arthur L Horwich.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nm.2468

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing