Cytochrome
            <i>c</i>
            folding pathway: Kinetic native-state hydrogen exchange

Hoang, Linh; Bédard, Sabrina; Mallela, Krishna; Yang, Lin; Englander, S. Walter

doi:10.1073/pnas.152439199

Cited by 117 publications

(158 citation statements)

References 40 publications

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“…These same foldon units have been repeatedly confirmed in multiple experiments under different conditions by HX pulse labeling (Krishna et al 2003a(Krishna et al , 2004b, by equilibrium NHX (Bai et al 1995b;Bai & Englander, 1996;Englander et al 1997;Krishna et al 2003bMaity et al 2005), and by a related kinetic NHX method that distinguishes concerted foldon units by virtue of their different unfolding rates rather than their different stabilities and m values (Hoang et al 2002;Krishna et al 2004a). …”

Section: 22mentioning

confidence: 78%

“…Some known foldons do encompass entire helical lengths (Bai et al 1995b;Fuentes & Wand, 1998a;Krishna et al 2003a;Feng et al 2005a) but others may not (Chamberlain et al 1996). Moreover, entire Ω-loops act as concerted unfolding units (Hoang et al 2002;Krishna et al 2003b), unsurprisingly so, because they are internally packed self-contained structures (Leszczynski & Rose, 1986). β-structures tend to break up into smaller separately cooperative units (Chamberlain et al 1996;Yan et al 2002Yan et al , 2004Bédard et al 2008).…”

Section: Foldon Structurementioning

confidence: 99%

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Protein folding and misfolding: mechanism and principles

Englander

Mayne

Mallela

2007

Quart. Rev. Biophys.

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172

267

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Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways. Optional misfolding errors are responsible for 3-state and heterogeneous kinetic folding. The protein folding problemThe search for protein folding pathways and the principles that guide them has proven to be one of the most difficult problems in all of structural biology. Biochemical pathways have almost universally been solved by isolating the pathway intermediates and determining their structures. This approach fails for protein folding pathways. Folding intermediates only live for <1 s and they cannot be isolated and studied by the usual structural methods.The protein folding problem has been attacked by the entire range of fast spectroscopic methods which are able to track folding in real time. Much valuable information has been obtained but mainly of a kinetic nature. Kinetic methods do not describe the structure of the

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Section: 22mentioning

confidence: 78%

Section: Foldon Structurementioning

confidence: 99%

Protein folding and misfolding: mechanism and principles

Englander

Mayne

Mallela

2007

Quart. Rev. Biophys.

Self Cite

172

267

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“…An example of the change in HX behavior as a function of protein concentration is shown in Figure 5B. As the protein concentration was increased, the apparent number of amide hydrogens exchanging through the fast, k f , process decreased and the number exchanging through the slow, k s , process increased for peptide 26-35, segment 31-47, and peptide [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]. No reliable trends were observed for the k i1 and k i2 processes for these peptides or segments.…”

Section: Experimental Analysismentioning

confidence: 99%

The Folding Energy Landscape of the Dimerization Domain of Escherichia coli Trp Repressor: A Joint Experimental and Theoretical Investigation

Simler

Levy

Onuchic

et al. 2006

Journal of Molecular Biology

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Enhanced structural insights into the folding energy landscape of the N-terminal dimerization domain of E. coli tryptophan repressor, 2 TR, were obtained from a combined experimental and theoretical analysis of its equilibrium folding reaction. Previous studies have shown that the three intertwined helices in [2-66] 2 TR are sufficient to drive the formation of a stable dimer for the fulllength protein, [2-107] 2 TR. The monomeric and dimeric folding intermediates that appear during the folding reactions of [2-66] 2 TR have counterparts in the folding mechanism of the full-length protein. The equilibrium unfolding energy surface on which the folding and dimerization reactions occur for [2-66] 2 TR was examined with a combination of native-state hydrogen exchange analysis, pepsin digestion and MALDI mass spectrometry performed at several protein and denaturant concentrations. Peptides corresponding to all three helices in [2-66] 2 TR show multi-layered protection patterns consistent with the relative stabilities of the dimeric and monomeric folding intermediates. The observation of protection exceeding that offered by the dimeric intermediate in segments from all three helices implies that a segment-swapping mechanism may be operative in the monomeric intermediate. Protection greater than that expected from the global stability for a single amide hydrogen in a peptide from the A-helix and another from the C-helix may reflect non-random structure, possibly a pre-cursor for segment swapping, in the urea-denatured state. Native topologybased model simulations that correspond to a funnel energy landscape capture both the monomeric and dimeric intermediates suggested by the HX-MS data and provide a rationale for the progressive acquisition of secondary structure in their conformational ensembles.

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“…The transition X 2 D involves rupture of the Fe-S(Met80) bond, its substitution with a linkage to another His residue (at neutral pH) or an H 2 O molecule (at acidic pH), loosening of the tryptophan-heme domain and an almost complete rearrangement of the polypeptide conformation of the protein. More recently, however, more complicated mechanisms have been proposed [14,[16][17][18][19][20][21]. Concerted unfolding units (foldons) have been claimed to determine the folding-unfolding behavior of cytochrome c [16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…More recently, however, more complicated mechanisms have been proposed [14,[16][17][18][19][20][21]. Concerted unfolding units (foldons) have been claimed to determine the folding-unfolding behavior of cytochrome c [16][17][18][19][20][21]. In particular the N-yellow X loop (residues 40-57) is suggested to be involved in the first step of the unfolding pathway [21].…”

Section: Introductionmentioning

confidence: 99%

Redox thermodynamics of cytochromes c subjected to urea induced unfolding

et al. 2009

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The thermodynamics of the electron transfer (ET) process for beef heart and yeast cytochromes c and the Lys72Ala/Lys73Ala/Lys79Ala mutant of the latter species subjected to progressive urea-induced unfolding was determined electrochemically. The results indicate the presence of at least three protein forms which were assigned to a low-temperature and a high-temperature HisMet intermediate species and a bis-histidinate form (although the presence of a His-Lys form cannot be excluded). The much lower E°0 value of the bis-histidinate conformer as compared to His-Met ligated species is largely determined by the enthalpic contribution induced by axial ligand substitution. The biphasic E°0 versus T profile for the His-Met species is due to a difference in reduction entropy between the conformers at low and high temperatures. Enthalpy-entropy compensation phenomena for the reduction reaction at varying urea concentration for all the forms of the investigated cytochromes c were addressed and discussed.

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Cytochrome c folding pathway: Kinetic native-state hydrogen exchange

Cited by 117 publications

References 40 publications

Protein folding and misfolding: mechanism and principles

Protein folding and misfolding: mechanism and principles

The Folding Energy Landscape of the Dimerization Domain of Escherichia coli Trp Repressor: A Joint Experimental and Theoretical Investigation

Redox thermodynamics of cytochromes c subjected to urea induced unfolding

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