The Burial of Solvent-Accessible Surface Area is a Predictor of Polypeptide Folding and Misfolding as a Function of Chain Elongation

Kurt, Neşe; Cavagnero, Silvia

doi:10.1021/ja0560682

Cited by 20 publications

(30 citation statements)

References 22 publications

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“…These investigations revealed that nascent single-domain proteins are not fully structured before they have entirely emerged from the ribosomal tunnel, consistent with the expectation that the C-terminal portion of the chain plays an important role in folding (49, 50). …”

Section: What a Difference Translation Makessupporting

confidence: 79%

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Protein Folding at the Exit Tunnel

Fedyukina

Cavagnero

2011

Annu. Rev. Biophys.

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Over five decades of research have yielded a large body of information on how purified proteins attain their native state when refolded in the test tube, starting from a chemically or thermally denatured state. Nevertheless, we still know little about how proteins fold and unfold in their natural biological habitat: the living cell. Indeed, a variety of cellular components, including molecular chaperones, the ribosome, and crowding of the intracellular medium, modulate folding mechanisms in physiologically relevant environments. This review focuses on the current state of knowledge in protein folding in the cell with emphasis on the early stage of a protein’s life, as the nascent polypeptide traverses and emerges from the ribosomal tunnel. Given the vectorial nature of ribosome-assisted translation, the transient degree of chain elongation becomes a relevant variable expected to affect nascent protein foldability, aggregation propensity and extent of interaction with chaperones and the ribosome.

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Section: What a Difference Translation Makessupporting

confidence: 79%

“…Analogous studies on chymotrypsin inhibitor 2 and barnase are in agreement with the above ideas (61). Computational studies based on the burial of nonpolar surface as a function of chain elongation further support this concept (49, 50). …”

Section: Folding On the Ribosome: What Is Special About It?mentioning

confidence: 88%

Protein Folding at the Exit Tunnel

Fedyukina

Cavagnero

2011

Annu. Rev. Biophys.

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“…The amide and hydrocarbon ASA results and structural analysis presented here provide strong experimental support for a general mechanism of protein folding in which most if not all of the native elements of secondary structure form before TS, and begin to coalesce into more native-like structures in TS, as previously proposed (2,4,(44)(45)(46). A rapidly equilibrating mixture of largely unfolded chains with various subsets of these elements of 2°structure comprises the ensemble of early folding intermediates.…”

Section: Analysis Of All-2°and More Advanced Structural Models Of Folsupporting

confidence: 77%

Probing the protein-folding mechanism using denaturant and temperature effects on rate constants

Guinn¹,

Kontur

Tsodikov

et al. 2013

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

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Protein folding has been extensively studied, but many questions remain regarding the mechanism. Characterizing early unstable intermediates and the high-free-energy transition state (TS) will help answer some of these. Here, we use effects of denaturants (urea, guanidinium chloride) and temperature on folding and unfolding rate constants and the overall equilibrium constant as probes of surface area changes in protein folding. We interpret denaturant kinetic m-values and activation heat capacity changes for 13 proteins to determine amounts of hydrocarbon and amide surface buried in folding to and from TS, and for complete folding. Predicted accessible surface area changes for complete folding agree in most cases with structurally determined values. We find that TS is advanced (50-90% of overall surface burial) and that the surface buried is disproportionately amide, demonstrating extensive formation of secondary structure in early intermediates. Models of possible pre-TS intermediates with all elements of the native secondary structure, created for several of these proteins, bury less amide and hydrocarbon surface than predicted for TS. Therefore, we propose that TS generally has both the native secondary structure and sufficient organization of other regions of the backbone to nucleate subsequent (post-TS) formation of tertiary interactions. The approach developed here provides proof of concept for the use of denaturants and other solutes as probes of amount and composition of the surface buried in coupled folding and other large conformational changes in TS and intermediates in protein processes.etermination of the mechanism of protein folding [unfolded (U) → folded (F)] is a long-standing goal of biophysical research. Folding of a single domain globular protein is a very highly cooperative (thermodynamically two-state) process. From analysis of folding kinetic data for CI2 and barnase, Fersht et al.(1) concluded that proteins fold through a high-free-energy transition state (TS) with partially formed elements of native structure. Recently, Barrick and Sosnick (2) concluded that an ensemble of unstable, rapidly reversible intermediates form early in the folding mechanism, and that the most advanced and unstable of these undergoes a rate-determining conformational change with transition state TS. This transit step, slower than the reverse direction of previous rapidly reversible steps, is followed by rapid propagation of folding. Most proposals for the initial intermediates invoke unstable regions of α-helix and/or β-sheet; these are thought to coalesce and/or rearrange to form TS. Kay and coworkers (3) characterized a marginally stable early intermediate of Fyn SH3 domain and found that interactions of amide groups formed earlier in the folding pathway than interactions of methyl groups, indicating that 2°structure formed before the 3°fold. Recent hydrogen exchange pulse-labeling experiments analyzed with mass spectrometry by Englander, Marqusee, and collaborators (4) indicate that folding of RNase H occurs t...

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“…Considerable effort has been devoted to the search for a general scale that might relate the physical properties of the side-chain of each the 20 amino acids to its solvent-accessible surface area in folded proteins (ASA fold ), as determined using a probe that is often a water-sized sphere (24)(25)(26)(27)(28)(29)(30)(31)(32). Values of ASA fold depend on the size and shape of the probe, the presence or absence of steric constraints on the approach of a probe that may be imposed by flanking peptide bonds, and the rotameric preferences of the larger side-chains, all of which can affect the normalization of estimated ASA values.…”

Section: Relationship Between Side-chain Transfer Equilibria and Proteinmentioning

confidence: 99%

Temperature dependence of amino acid hydrophobicities

Wolfenden

Lewis

Yuan

et al. 2015

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

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The hydrophobicities of the 20 common amino acids are reflected in their tendencies to appear in interior positions in globular proteins and in deeply buried positions of membrane proteins. To determine whether these relationships might also have been valid in the warm surroundings where life may have originated, we examined the effect of temperature on the hydrophobicities of the amino acids as measured by the equilibrium constants for transfer of their side-chains from neutral solution to cyclohexane (K w>c ). The hydrophobicities of most amino acids were found to increase with increasing temperature. Because that effect is more pronounced for the more polar amino acids, the numerical range of K w>c values decreases with increasing temperature. There are also modest changes in the ordering of the more polar amino acids. However, those changes are such that they would have tended to minimize the otherwise disruptive effects of a changing thermal environment on the evolution of protein structure. Earlier, the genetic code was found to be organized in such a way that-with a single exception (threonine)-the side-chain dichotomy polar/ nonpolar matches the nucleic acid base dichotomy purine/pyrimidine at the second position of each coding triplet at 25°C. That dichotomy is preserved at 100°C. The accessible surface areas of amino acid side-chains in folded proteins are moderately correlated with hydrophobicity, but when free energies of vapor-tocyclohexane transfer (corresponding to size) are taken into consideration, a closer relationship becomes apparent.T he equilibrium conformations of proteins in neutral solution are strongly influenced by interactions between their constituent amino acids and solvent water. Early work on the crystal structure of hemoglobin and related proteins showed that the side-chains of the more polar amino acid residues tend to be exposed to solvent, whereas less polar side-chains tend to be buried within the interior of globular proteins (1). Later, those tendencies were put to a quantitative test by measuring equilibria of transfer of amino acid side-chains from neutral aqueous solution into less polar environments, such as the vapor phase (2, 3) or a nonpolar solvent such as cyclohexane (4), which dissolves only ∼2 × 10 −3 M water at saturation (5) and appears to be devoid of specific interactions with solutes. The water-to-cyclohexane distribution coefficients (K w>c ) of the 20 common sidechains [here termed "hydrophobicities" (6, 7) and expressed in concentration units of mol/L in each phase; SI Appendix] were found to span a range of 15 orders of magnitude at pH 7 and 25°C. Values of K w>c have been shown to be related to their outside-to-inside distributions in globular proteins (4,8) and to their tendencies to appear within the buried sequences of transmembrane proteins (9-11).Those solvent distribution experiments were conducted at what we would consider ordinary temperatures. However, there is widespread (12, 13)-if not universal (14)-agreement that life originated when the ea...

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The Burial of Solvent-Accessible Surface Area is a Predictor of Polypeptide Folding and Misfolding as a Function of Chain Elongation

Cited by 20 publications

References 22 publications

Protein Folding at the Exit Tunnel

Protein Folding at the Exit Tunnel

Probing the protein-folding mechanism using denaturant and temperature effects on rate constants

Temperature dependence of amino acid hydrophobicities

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