Intermediates: Ubiquitous Species on Folding Energy Landscapes?

Overview

Journal Curr Opin Struct Biol

Date 2007 Jan 24

PMID 17239580

Citations 88

Authors

David J Brockwell

Sheena E Radford

Affiliations

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Abstract

Although intermediates have long been recognised as fascinating species that form during the folding of large proteins, the role that intermediates play in the folding of small, single-domain proteins has been widely debated. Recent discoveries using new, sensitive methods of detection and studies combining simulation and experiment have now converged on a common vision for folding, involving intermediates as ubiquitous stepping stones en route to the native state. The results suggest that the folding energy landscapes of even the smallest proteins possess significant ruggedness in which intermediates stabilized by both native and non-native interactions are common features.

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References

Yang M, Lei M, Bruschweiler R, Huo S . Initial conformational changes of human transthyretin under partially denaturing conditions. Biophys J. 2005; 89(1):433-43. PMC: 1366544. DOI: 10.1529/biophysj.105.059642. View

Nishimura C, Lietzow M, Dyson H, Wright P . Sequence determinants of a protein folding pathway. J Mol Biol. 2005; 351(2):383-92. DOI: 10.1016/j.jmb.2005.06.017. View

Englander S . Protein folding intermediates and pathways studied by hydrogen exchange. Annu Rev Biophys Biomol Struct. 2000; 29:213-38. DOI: 10.1146/annurev.biophys.29.1.213. View

Nauli S, Kuhlman B, Baker D . Computer-based redesign of a protein folding pathway. Nat Struct Biol. 2001; 8(7):602-5. DOI: 10.1038/89638. View

Palmer 3rd A, Kroenke C, Loria J . Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol. 2001; 339:204-38. DOI: 10.1016/s0076-6879(01)39315-1. View

Capaldi A, Kleanthous C, Radford S . Im7 folding mechanism: misfolding on a path to the native state. Nat Struct Biol. 2002; 9(3):209-16. DOI: 10.1038/nsb757. View

Fersht A, Daggett V . Protein folding and unfolding at atomic resolution. Cell. 2002; 108(4):573-82. DOI: 10.1016/s0092-8674(02)00620-7. View

Chu R, Pei W, Takei J, Bai Y . Relationship between the native-state hydrogen exchange and folding pathways of a four-helix bundle protein. Biochemistry. 2002; 41(25):7998-8003. DOI: 10.1021/bi025872n. View

Teilum K, Maki K, Kragelund B, Poulsen F, Roder H . Early kinetic intermediate in the folding of acyl-CoA binding protein detected by fluorescence labeling and ultrarapid mixing. Proc Natl Acad Sci U S A. 2002; 99(15):9807-12. PMC: 125024. DOI: 10.1073/pnas.152321499. View

10.

Sanchez I, Kiefhaber T . Evidence for sequential barriers and obligatory intermediates in apparent two-state protein folding. J Mol Biol. 2002; 325(2):367-76. DOI: 10.1016/s0022-2836(02)01230-5. View

11.

Friel C, Capaldi A, Radford S . Structural analysis of the rate-limiting transition states in the folding of Im7 and Im9: similarities and differences in the folding of homologous proteins. J Mol Biol. 2003; 326(1):293-305. DOI: 10.1016/s0022-2836(02)01249-4. View

12.

Head-Gordon T, Brown S . Minimalist models for protein folding and design. Curr Opin Struct Biol. 2003; 13(2):160-7. DOI: 10.1016/s0959-440x(03)00030-7. View

13.

Gianni S, Guydosh N, Khan F, Caldas T, Mayor U, White G . Unifying features in protein-folding mechanisms. Proc Natl Acad Sci U S A. 2003; 100(23):13286-91. PMC: 263785. DOI: 10.1073/pnas.1835776100. View

14.

Spudich G, Miller E, Marqusee S . Destabilization of the Escherichia coli RNase H kinetic intermediate: switching between a two-state and three-state folding mechanism. J Mol Biol. 2003; 335(2):609-18. DOI: 10.1016/j.jmb.2003.10.052. View

15.

Gorski S, Le Duff C, Capaldi A, Kalverda A, Beddard G, Moore G . Equilibrium hydrogen exchange reveals extensive hydrogen bonded secondary structure in the on-pathway intermediate of Im7. J Mol Biol. 2004; 337(1):183-93. DOI: 10.1016/j.jmb.2004.01.004. View

16.

Vu N, Feng H, Bai Y . The folding pathway of barnase: the rate-limiting transition state and a hidden intermediate under native conditions. Biochemistry. 2004; 43(12):3346-56. DOI: 10.1021/bi0362267. View

17.

Mogensen J, Ipsen H, Holm J, Otzen D . Elimination of a misfolded folding intermediate by a single point mutation. Biochemistry. 2004; 43(12):3357-67. DOI: 10.1021/bi0358622. View

18.

Mason J, Cliff M, Sessions R, Clarke A . Low energy pathways and non-native interactions: the influence of artificial disulfide bridges on the mechanism of folding. J Biol Chem. 2005; 280(49):40494-9. DOI: 10.1074/jbc.M509281200. View

19.

Nishimura C, Dyson H, Wright P . Identification of native and non-native structure in kinetic folding intermediates of apomyoglobin. J Mol Biol. 2005; 355(1):139-56. DOI: 10.1016/j.jmb.2005.10.047. View

20.

Grey M, Tang Y, Alexov E, McKnight C, Raleigh D, Palmer 3rd A . Characterizing a partially folded intermediate of the villin headpiece domain under non-denaturing conditions: contribution of His41 to the pH-dependent stability of the N-terminal subdomain. J Mol Biol. 2005; 355(5):1078-94. DOI: 10.1016/j.jmb.2005.11.001. View