Universal Nature of Collapsibility in the Context of Protein Folding and Evolution

Thirumalai, D.; Samanta, Himadri S.; Maity, Hiranmay; Reddy, Gunda

doi:10.1016/j.tibs.2019.04.003

Cited by 34 publications

(44 citation statements)

References 86 publications

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“…At L = 316, the nascent chain has properties of an intrinsically disordered protein, whereas the addition of just 12 amino acids to L = 328 results in the formation of collapsed or partially structured states and subsequent folding to the native structure. Theoretical studies concluded that the formation of compact states is an evolved property of natural proteins 47 . The G-domain may be an attractive model to investigate how this property is related to protein sequence and structure.…”

Section: Discussionmentioning

confidence: 99%

Synthesis runs counter to directional folding of a nascent protein domain

Chen

Rajasekaran

Liu

et al. 2020

Preprint

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Folding of individual domains in large proteins occurs during translation, helping to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the G-domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway that initiates from the C-terminus and thus runs counter to synthesis. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

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Section: Discussionmentioning

confidence: 99%

Synthesis runs counter to directional folding of a nascent protein domain

Chen

Rajasekaran

Liu

et al. 2020

Preprint

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“…The value of ν suggests that Aβ monomers behave as polymers in a good solvent. However, we should note that ν estimates from either simulations or experiments suffer from finite-size effects (56).…”

Section: Few Metastable States Cannot Represent the Aβ Ensemblesmentioning

confidence: 99%

Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their distinct aggregation propensities

Chakraborty¹,

Straub

Thirumalai³

2020

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of 17Cluster 5Cluster 6 Cluster 8 Cluster 12 Cluster 1+2+3+7 Fig. S8. Clusters 4,5,6,8: Conformational clusters in Aβ40 with conformations with different extents of residual structuring near the N-terminus. Residues 1-10, which are disordered in the fibril structure, are shown in magenta, and residues 11-40, which are ordered in the fibril structure, are shown in light green. These clusters also consist of RC-like structures (see Table S3). The supercluster formed by clusters 1,2,3 and 7 consists of exclusively RC-like structures, and is characterized by a featureless contact map. Clusters in which the conformations with structural signatures of the fibril state are shown in the main text. 13 of 17Cluster 1Cluster 10Cluster 11 Cluster 2+3+8+9 Fig. S9. Different cluster families constituting the Aβ42 monomer ensemble. In cluster 1, the conformations have some structure in the C-terminus. Cluster 10 consists of structures with an ordered N-terminus. In cluster 11, both the termini are disordered. However, some residual structure is present near the middle of the peptide. In these clusters, residues 1-16, which form the disordered region in the fibril structure are shown in magenta, and residues 17-42, which form the ordered region of the fibril, are in green. These clusters also consist of RC-like conformations in addition to those exhibiting different extents of residual structuring. The supercluster formed by clusters 2,3,8 and 9 has a featureless contact map, and consists of exclusively RC-like conformations. The clusters which contain structures that have some resemblance to the monomer units of different Aβ42 polymorphs are shown in the main text.

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“…(ii) It should be noted that the change in the mean value of R g , with respect to the unfolded states is less than about 20%, which is a common observation in a number of proteins. 60 Our results show that it is difficult to unambiguously assess barriers to collapse in folding. In light of extensive theoretical studies, summarized elsewhere, 60 we surmise that the barrier to collapse in Cyt c should exist 56 but multiple probes might be needed to estimate the magnitude.…”

Section: Resultsmentioning

confidence: 84%

Dramatic shape changes occur as Cytochrome c folds

Kırmızıaltın

Pitici²,

Cárdenas

et al. 2020

Preprint

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Extensive experimental studies on the folding of Cytochrome c (Cyt c) make this small protein an ideal target for atomic detailed simulations for the purposes of quantitatively characterizing the structural transitions and the associated time scales for folding to the native state from an ensemble of unfolded states. We use previously generated atomically detailed folding trajectories by the Stochastic Difference Equation in Length (SDEL) to calculate the time-dependent changes in the Small Angle X-ray scattering (SAXS) profiles.Excellent agreement is obtained between experiments and simulations for the time dependent SAXS spectra, allowing us to identify the structures of the folding intermediates, which shows that Cyt c reaches the native state by a sequential folding mechanism. Using the ensembles of structures along the folding pathways we show that compaction and the sphericity of Cyt c change dramatically from the prolate ellipsoid shape in the unfolded 1 state to the spherical native state. Our data, which provides unprecedented quantitative agreement with all aspects of time-resolved SAXS experiments, shows that hydrophobic collapse and amide group protection coincide on the 100 microseconds time scale, which is in accord with ultrafast Hydrogen/Deuterium exchange studies. Based on these results we propose that compaction of polypeptide chains, accompanied by dramatic shape changes, is a universal characteristic of globular proteins, regardless of the underlying folding mechanism.

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Universal Nature of Collapsibility in the Context of Protein Folding and Evolution

Cited by 34 publications

References 86 publications

Synthesis runs counter to directional folding of a nascent protein domain

Synthesis runs counter to directional folding of a nascent protein domain

Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their distinct aggregation propensities

Dramatic shape changes occur as Cytochrome c folds

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