Structure of the transition state for the folding/unfolding of the barley chymotrypsin inhibitor 2 and its implications for mechanisms of protein folding.

Otzen, Daniel E.; Itzhaki, Laura S.; elMasry, Nadia; Jackson, Sophie; Fersht, Alan R.

doi:10.1073/pnas.91.22.10422

Cited by 216 publications

(197 citation statements)

References 36 publications

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“…For smaller proteins, such as the chymotrypsin inhibitor 2, only one unit is generated. For larger proteins, several hydrophobic folding units are automatically obtained, and often more than one hydrophobic folding unit is generated for a domain (e.g., four units for actin), consistent with the projection that in larger proteins, formation of a domain may be preceded by a collapsed, rearranged, hydrophobic module (Otzen et al, 1994). Whereas some hydrophobic folding units are straightforwardly identified by our algorithm, others are more difficult to discern.…”

supporting

confidence: 57%

“…Consequently, a native globular protein generally displays a compact structure, containing a hydrophobic interior. For the smaller proteins, this native structure has been proposed to be achieved via a two-state kinetic model Otzen et al, 1994). This, however, may not be the case for the larger proteins, where the initial fast step may involve collapse of the hydrophobic cores with subsequent rearrangement to yield some fully formed secondary structure elements along with tertiary structure interactions.…”

mentioning

confidence: 99%

“…469 Alternatively, secondary structure elements may form late in the folding pathway (Otzen et al, 1994). The slower step apparently involves attaining the native conformation via the pairing of the already largely pre-folded domains or folding units.…”

mentioning

confidence: 99%

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Hydrophobic folding units derived from dissimilar monomer structures and their interactions

Tsai

Nussinov

1997

Protein Science

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We have designed an automated procedure to cut a protein into compact hydrophobic folding units. The hydrophobic units are large enough to contain tertiary non-local interactions, reflecting potential nucleation sites during protein folding. The quality of a hydrophobic folding unit is evaluated by four criteria. The first two correspond to visual characterization of a structural domain, namely, compactness and extent of isolation. We use the definition of Zehfus and Rose (Zehfus MH, Rose GD, 1986, Biochemistry 25:335-340) to calculate the compactness of a cut protein unit. The isolation of a unit is based on the solvent accessible surface area (ASA) originally buried in the interior and exposed to the solvent after cutting. The third quantity is the hydrophobicity, equivalent to the fraction of the buried non-poiar ASA with respect to the total non-polar ASA. The last criterion in the evaluation of a folding unit is the number of segments it includes. To conform with the rationale of obtaining hydrophobic units, which may relate to early folding events, the hydrophobic interactions are implicitly and explicitly applied in their generation and assessment. We follow Holm and Sander (Holm L, Sander C, 1994, Proteins 19:256-268) to reduce the multiple cutting-point problem to a one-dimensional search for all reasonable trial cuts. However, as here we focus on the hydrophobic cores, the contact matrix used to obtain the first non-trivial eigenvector contains only hydrophobic contacts, rather than all, hydrophobic and hydrophilic, interactions. This dataset of hydrophobic folding units, derived from structurally dissimilar single chain monomers, is particularly useful for investigations of the mechanism of protein folding. For cases where there are kinetic data, the one or more hydrophobic folding units generated for a protein correlate with the two or with the three-state folding process observed. We carry out extensive amino acid sequence order independent structural comparisons to generate a structurally non-redundant set of hydrophobic folding units for fold recognition and for statistical purposes.

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supporting

confidence: 57%

mentioning

confidence: 99%

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Hydrophobic folding units derived from dissimilar monomer structures and their interactions

Tsai

Nussinov

1997

Protein Science

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“…Fersht and coworkers found that specific interactions in the folding nucleus are equally important determinants of folding rates. For example, mutations in the folding nucleus of CI2 did not change its contact order, but result in a three order magnitude increase in the folding rate [90,121,122]. Sequence-based prediction of folding rates has also been proposed and was found to be of comparable performance to that of contact order [123,124].…”

Section: Protein Folding Kineticsmentioning

confidence: 99%

“…CI2 transition state has secondary, tertiary structure elements [121]. Native topology and hydrogen bonds mediates SH3 folding [250,251].…”

Section: Mechanism Of Folding/ Unfoldingmentioning

confidence: 99%

Protein folding: Then and now

Chen

Ding

Nie

et al. 2008

Archives of Biochemistry and Biophysics

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Over the past three decades the protein folding field has undergone monumental changes. Originally a purely academic question, how a protein folds has now become vital in understanding diseases and our abilities to rationally manipulate cellular life by engineering protein folding pathways. We review and contrast past and recent developments in the protein folding field. Specifically, we discuss the progress in our understanding of protein folding thermodynamics and kinetics, the properties of evasive intermediates, and unfolded states. We also discuss how some abnormalities in protein folding lead to protein aggregation and human diseases.

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Molecular collapse: The rate-limiting step in two-state cytochrome c folding

1996

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Structure of the transition state for the folding/unfolding of the barley chymotrypsin inhibitor 2 and its implications for mechanisms of protein folding.

Abstract: The equilibrium and kinetics of folding of the single-domain protein chy yp hibItor 2 conform to the simple two-state ode.

Cited by 216 publications

References 36 publications

Hydrophobic folding units derived from dissimilar monomer structures and their interactions

Hydrophobic folding units derived from dissimilar monomer structures and their interactions

Protein folding: Then and now

Molecular collapse: The rate-limiting step in two-state cytochrome c folding

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