A noncovalent peptide complex as a model for an early folding intermediate of cytochrome c

Wu, Lawren C.; Laub, Paul B.; Elöve, Gülnur A.; Carey, Jannette; Röder, Heinrich

doi:10.1021/bi00089a050

Cited by 112 publications

(99 citation statements)

References 39 publications

(48 reference statements)

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“…Kinetic experiments detected pathway intermediates that were interpreted in these terms Baldwin 1982, 1990). In agreement, a range of structural experiments characterized partially folded forms, molten globules, and folded protein fragments believed to mimic specific kinetic folding intermediates (Oas and Kim 1988;Staley and Kim 1990;Wu et al 1993;Ptitsyn 1995;Chamberlain et al 1999;Feng et al 2005;Maity et al 2005). Structural information from hydrogen exchange and related methods found and characterized partially native-like intermediates and showed that they construct classical folding pathways (Roder et al 1988;Bai et al 1995;Chamberlain et al 1996;Fuentes and Wand 1998a,b;Xu et al 1998;Milne et al 1999;Chamberlain and Marqusee 2000;Chu et al 2002;Hoang et al 2002;Silverman and Harbury 2002;Yan et al 2002Yan et al , 2004Feng et al 2003Feng et al , 2005Krishna et al 2003aKrishna et al ,b, 2004Krishna et al , 2006Maity et al 2004Maity et al , 2005Cecconi et al 2005;Weinkam et al 2005).…”

Section: Discussionmentioning

confidence: 79%

A unified mechanism for protein folding: Predetermined pathways with optional errors

Mallela

Englander

2007

Protein Science

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There is a fundamental conflict between two different views of how proteins fold. Kinetic experiments and theoretical calculations are often interpreted in terms of different population fractions folding through different intermediates in independent unrelated pathways (IUP model). However, detailed structural information indicates that all of the protein population folds through a sequence of intermediates predetermined by the foldon substructure of the target protein and a sequential stabilization principle. These contrary views can be resolved by a predetermined pathway-optional error (PPOE) hypothesis. The hypothesis is that any pathway intermediate can incorporate a chance misfolding error that blocks folding and must be reversed for productive folding to continue. Different fractions of the protein population will then block at different steps, populate different intermediates, and fold at different rates, giving the appearance of multiple unrelated pathways. A test of the hypothesis matches the two models against extensive kinetic folding results for hen lysozyme which have been widely cited in support of independent parallel pathways. The PPOE model succeeds with fewer fitting constants. The fitted PPOE reaction scheme leads to known folding behavior, whereas the IUP properties are contradicted by experiment. The appearance of a conflict with multipath theoretical models seems to be due to their different focus, namely on multitrack microscopic behavior versus cooperative macroscopic behavior. The integration of three well-documented principles in the PPOE model (cooperative foldons, sequential stabilization, optional errors) provides a unifying explanation for how proteins fold and why they fold in that way.Keywords: protein folding; misfolding; foldons; sequential stabilization; optional error; predetermined pathway; lysozyme Detailed structural information obtained from hydrogen exchange (HX) studies of cytochrome c (Cyt c) and related studies with other proteins support a classical view of protein folding in which all of the molecules in a refolding population fold through essentially the same intermediate structures (Chamberlain and Marqusee 2000;Englander 2000;Maity et al. 2005). The pathway constructs the native protein by the stepwise addition of the cooperative folding units of the native structure, called foldons. The order of pathway steps is guided by a sequential stabilization process in which prior native-like structure templates the formation of subsequent complementary structure. Thus the folding pathway is determined by the same cooperative interactions that determine the target native structure. The pathway may be linear or may branch at any step as directed by the logic of the sequential stabilization process (Krishna et al. 2006 449quite differently, in terms of independent unrelated pathways (IUP model). Proteins can fold in a simple two-state way with only the unfolded (U) and native (N) states significantly populated, or in a multistate way with one or more intermediates (...

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Section: Discussionmentioning

confidence: 79%

A unified mechanism for protein folding: Predetermined pathways with optional errors

Mallela

Englander

2007

Protein Science

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“…For example, in cyt c folding, the first-formed PUF (blue foldon folded, Fig. 1B) is more stable than the unfolded state by almost 3 kcal/mol in free energy (60), even though the isolated blue foldon is much less stable (61,62). In RNase H folding the first two foldons seem unlikely to be stable in isolation (see model in Fig.…”

Section: Results and Considerationsmentioning

confidence: 99%

The case for defined protein folding pathways

Englander

Mayne

2017

Proc. Natl. Acad. Sci. U.S.A.

126

143

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We consider the differences between the many-pathway protein folding model derived from theoretical energy landscape considerations and the defined-pathway model derived from experiment. A basic tenet of the energy landscape model is that proteins fold through many heterogeneous pathways by way of amino acid-level dynamics biased toward selecting native-like interactions. The many pathways imagined in the model are not observed in the structureformation stage of folding by experiments that would have found them, but they have now been detected and characterized for one protein in the initial prenucleation stage. Analysis presented here shows that these many microscopic trajectories are not distinct in any functionally significant way, and they have neither the structural information nor the biased energetics needed to select native vs. nonnative interactions during folding. The opposed defined-pathway model stems from experimental results that show that proteins are assemblies of small cooperative units called foldons and that a number of proteins fold in a reproducible pathway one foldon unit at a time. Thus, the same foldon interactions that encode the native structure of any given protein also naturally encode its particular foldon-based folding pathway, and they collectively sum to produce the energy bias toward native interactions that is necessary for efficient folding. Available information suggests that quantized native structure and stepwise folding coevolved in ancient repeat proteins and were retained as a functional pair due to their utility for solving the difficult protein folding problem.protein folding | foldons | energy landscape theory P rotein folding is among the most important reactions in all of biology. However, 50 y after C. B. Anfinsen showed that proteins can fold spontaneously without outside help (1, 2), and despite the intensive work of thousands of researchers leading to more than five publications per day in the current literature, there is still no general agreement on the most primary questions (3-5). How do proteins fold? Why do they fold in that way? How is the course of folding encoded in a 1D amino acid sequence? These questions have fundamental significance for protein science and its numerous applications. Over the years these questions have generated a large literature leading to different models for the folding process.The "new view" folding model, derived from hypothetical energy landscape and statistical mechanical considerations (6-12), proposes that folding proteins navigate to their native state through very many independent pathways. The many trajectories in Fig. 1A imply an unfolded protein conformationally searching for its lowestenergy native state by way of dynamic bond rotations in a way that is guided by its energy landscape, as for any chemical reaction. For effective performance, folding proteins must "know" how to select native as opposed to nonnative interactions. This information is said to be contained in the shape of the energy landscape, but how it is ...

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“…Low and high pH (coupled with high ionic strength), low concentrations of guanidine and urea, and even various organic solvents have all been used to partially unfold proteins. The second approach studies the solution conformation and interactions of protein fragments (Brown and Klee, 1971;Baldwin, 1986;Sancho eta/., 1992;Wu et al, 1993;Waltho et al, 1993). The third approach uses quenched-flow, stopped-flow, or some other kinetic method to study the folding transients in real time (Ptitsyn, 1987;Kuwajima, 1989;Barrick and Baldwin, 1993;Baldwin, 1993;C.…”

Section: Introductionmentioning

confidence: 99%