Proteins in 6 m Guanidine Hydrochloride

Tanford, Charles; Kawahara, Kazuo; Lapanje, Savo

doi:10.1016/s0021-9258(18)96726-8

Cited by 187 publications

(42 citation statements)

References 8 publications

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“…59,60 To answer these questions, some used chemically denatured states that can be probed experimentally more easily and the molecular dimensions of these states appear to be consistent with those expected for random coils in some cases. 61,62 On the other hand, there are several studies that demonstrate the presence of specific local, native-like conformations under different conditions. 63,64 Discrete molecular dynamics (DMD) simulation studies (that use discretized energy potentials and fast event-sorting techniques to speed up MD simulation) of thermally denatured states attempted to bring about a reconciliation of these seemingly controversial properties of denatured proteins.…”

Section: Describing Disordered State Ensemblesmentioning

confidence: 99%

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

et al. 2016

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Understanding signaling and other complex biological processes requires elucidating the critical roles of intrinsically disordered proteins and regions (IDPs/IDRs), which represent ~30% of the proteome and enable unique regulatory mechanisms. In this review we describe the structural heterogeneity of disordered proteins that underpins these mechanisms and the latest progress in obtaining structural descriptions of ensembles of disordered proteins that are needed for linking structure and dynamics to function. We describe the diverse interactions of IDPs that can have unusual characteristics such as “ultrasensitivity” and “regulated folding and unfolding”. We also summarize the mounting data showing that large-scale assembly and protein phase separation occurs within a variety of signaling complexes and cellular structures. In addition, we discuss efforts to therapeutically target disordered proteins with small molecules. Overall, we interpret the remodeling of disordered state ensembles due to binding and post-translational modifications within an expanded framework for allostery that provides significant insights into how disordered proteins transmit biological information.

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Section: Describing Disordered State Ensemblesmentioning

confidence: 99%

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

et al. 2016

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“…There is an ongoing debate − on whether the denatured ensemble of single domain proteins undergoes a coil to globule transition during the burst phase of folding as the denaturant concentration is diluted to lower values. Proteins are heteropolymers and behave like random coils at high temperatures or denaturant concentrations. − An interesting question is whether proteins akin to polymers undergo a collapse transition in the burst phase of folding as the conditions are made conducive for folding. − Single domain proteins unlike polymers are finite sized and are composed of a specific sequence of amino acids which are hydrophobic and hydrophilic in character. The finite size effects and heteropolymer character are the reasons attributed to the marginal stability of proteins and the near overlap of the collapse and folding transition temperatures, which makes them fold efficiently. , …”

Section: Introductionmentioning

confidence: 99%

Folding of Protein L with Implications for Collapse in the Denatured State Ensemble

Maity

Reddy

2016

J. Am. Chem. Soc.

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A fundamental question in protein folding is whether the coil to globule collapse transition occurs during the initial stages of folding (burst-phase) or simultaneously with the protein folding transition. Single molecule fluorescence resonance energy transfer (FRET) and small angle X-ray scattering (SAXS) experiments disagree on whether Protein L collapse transition occurs during the burst-phase of folding. We study Protein L folding using a coarse-grained model and molecular dynamics simulations. The collapse transition in Protein L is found to be concomitant with the folding transition. In the burst-phase of folding, we find that FRET experiments overestimate radius of gyration, R g , of the protein due to the application of Gaussian polymer chain end-to-end distribution to extract R g from the FRET efficiency. FRET experiments estimate ≈ 6Å decrease in R g when the actual decrease is ≈ 3Å on Guanidinium Chloride denaturant dilution from 7.5M to 1M, and thereby suggesting pronounced compaction in the protein dimensions in the burst-phase.The ≈ 3Å decrease is close to the statistical uncertainties of the R g data measured from SAXS experiments, which suggest no compaction, leading to a disagreement with the FRET experiments.

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“…A random polymer model has been successfully used to describe the hydrodynamic dimensions of chemically unfolded proteins that are ordered in their native state. [17][18][19][20][21] A simple power law relationship can be used to predict the radius of gyration (R g ) for such proteins based solely on polymer length. 17,18 There is a growing consensus that this model cannot be accurately applied to IDPs because of the obvious compositional and physicochemical differences between the chemically unfolded states of ordered proteins and the native states of IDPs.…”

Section: Introductionmentioning

confidence: 99%

Understanding the structural ensembles of a highly extended disordered protein

et al. 2012

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Developing a comprehensive description of the equilibrium structural ensembles for intrinsically disordered proteins (IDPs) is essential to understanding their function. The p53 transactivation domain (p53TAD) is an IDP that interacts with multiple protein partners and contains numerous phosphorylation sites. Multiple techniques were used to investigate the equilibrium structural ensemble of p53TAD in its native and chemically unfolded states. The results from these experiments show that the native state of p53TAD has dimensions similar to a classical random coil while the chemically unfolded state is more extended. To investigate the molecular properties responsible for this behavior, a novel algorithm that generates diverse and unbiased structural ensembles of IDPs was developed. This algorithm was used to generate a large pool of plausible p53TAD structures that were reweighted to identify a subset of structures with the best fit to small angle X-ray scattering data. High weight structures in the native state ensemble show features that are localized to protein binding sites and regions with high proline content. The features localized to the protein binding sites are mostly eliminated in the chemically unfolded ensemble; while, the regions with high proline content remain relatively unaffected. Data from NMR experiments support these results, showing that residues from the protein binding sites experience larger environmental changes upon unfolding by urea than regions with high proline content. This behavior is consistent with the urea-induced exposure of nonpolar and aromatic side-chains in the protein binding sites that are partially excluded from solvent in the native state ensemble.

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Proteins in 6 m Guanidine Hydrochloride

Cited by 187 publications

References 8 publications

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

Folding of Protein L with Implications for Collapse in the Denatured State Ensemble

Understanding the structural ensembles of a highly extended disordered protein

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