scholarly journals Breaking the Deadlock of Molecular Chaperones

2017 ◽  
Author(s):  
Tania Morán Luengo ◽  
Roman Kityk ◽  
Matthias P. Mayer ◽  
Stefan G. D. Rüdiger
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones ◽  
Binding Pocket ◽  
Folding Pathway ◽  
Hydrophobic Core ◽  
Folding Intermediate ◽  
Native State ◽  
Folding Nucleus ◽  
Hydrophobic Binding ◽  
Highly Hydrophobic

AbstractProtein folding in the cell requires ATP-driven chaperone machines. It is poorly understood, however, how these machines fold proteins. Here we propose that the conserved Hsp70 and Hsp90 chaperones support formation of the folding nucleus by providing a gradient of decreasing hydrophobicity. Early on the folding pathway Hsp70 uses its highly hydrophobic binding pocket to recover a stalled, unproductive folding intermediate. The aggressive nature of Hsp70 action, however, blocks productive folding by grabbing hydrophobic, core-forming segments. This precludes on-pathway nucleation at high, physiological Hsp70 levels. Transfer to the less hydrophobic Hsp90 enables the intermediate to resume forming its folding nucleus. Subsequently, the protein enters a spontaneous folding trajectory towards its native state, independent of the ATPase activities of both Hsp70 and Hsp90. Our findings provide a general mechanistic concept for chaperoned protein folding.

scholarly journals GroEL/ES buffers entropic traps in folding pathway during evolution of a model substrate

2020 ◽  
Author(s):  
Anwar Sadat ◽  
Satyam Tiwari ◽  
Kanika Verma ◽  
Arjun Ray ◽  
Mudassar Ali ◽  
...  
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones ◽  
Folding Pathway ◽  
Substrate Protein ◽  
Model Protein ◽  
Physical Barriers ◽  
Evolutionary Step ◽  
Entropic Traps

ABSTRACTThe folding landscape of proteins can change during evolution with the accumulation of mutations that may introduce entropic or enthalpic barriers in the protein folding pathway, making it a possible substrate of molecular chaperones in vivo. Can the nature of such physical barriers of folding dictate the feasibility of chaperone-assistance? To address this, we have simulated the evolutionary step to chaperone-dependence keeping GroEL/ES as the target chaperone and GFP as a model protein in an unbiased screen. We find that the mutation conferring GroEL/ES dependence in vivo and in vitro encode an entropic trap in the folding pathway rescued by the chaperonin. Additionally, GroEL/ES can edit the formation of non-native contacts similar to DnaK/J/E machinery. However, this capability is not utilized by the substrates in vivo. As a consequence, GroEL/ES caters to buffer mutations that predominantly cause entropic traps, despite possessing the capacity to edit both enthalpic and entropic traps in the folding pathway of the substrate protein.

scholarly journals Unfolding the chaperone story

2017 ◽  
Vol 28 (22) ◽  
pp. 2919-2923 ◽  
Author(s):  
F. Ulrich Hartl
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones ◽  
Current Concept ◽  
Cellular Process ◽  
Protein Chain ◽  
Native State ◽  
Folding Process ◽  
Spontaneous Process ◽  
Short Essay

Protein folding in the cell was originally assumed to be a spontaneous process, based on Anfinsen’s discovery that purified proteins can fold on their own after removal from denaturant. Consequently cell biologists showed little interest in the protein folding process. This changed only in the mid and late 1980s, when the chaperone story began to unfold. As a result, we now know that in vivo, protein folding requires assistance by a complex machinery of molecular chaperones. To ensure efficient folding, members of different chaperone classes receive the nascent protein chain emerging from the ribosome and guide it along an ordered pathway toward the native state. I was fortunate to contribute to these developments early on. In this short essay, I will describe some of the critical steps leading to the current concept of protein folding as a highly organized cellular process.

scholarly journals A protein folding intermediate pulls its weight

2020 ◽  
Vol 295 (33) ◽  
pp. 11418-11419
Author(s):  
Jonathan P. Schlebach
Keyword(s):  
Protein Folding ◽  
Protein Synthesis ◽  
Rnase H ◽  
Biased Sampling ◽  
Folding Pathway ◽  
Folding Intermediate ◽  
Native Structure ◽  
Unfolded Proteins ◽  
Biochemical Function ◽  
Folding Pathways

Proteins must acquire and maintain a specific fold to execute their biochemical function(s). In solution, unfolded proteins typically find this native structure through a biased sampling of preferred intermediate conformations. However, the initial search for these structures begins during protein synthesis, and it is unclear how much interactions between the ribosome and nascent polypeptide skew folding pathways. In this issue, Jensen and colleagues use a ribosomal force–profiling assay to show that RNase H forms a similar folding intermediate on and off the ribosome. In conjunction with measurements of the rate of RNase H unfolding on and off the ribosome, their results show that ribosomal interactions have little impact on the folding pathway of RNase H. These findings suggest that the ribosome itself does not necessarily rewire protein folding reactions.

scholarly journals Comparative Assessment of NMR Probes for the Experimental Description of Protein Folding Pathways with High-Pressure NMR

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 656
Author(s):  
Vincent Van Deuren ◽  
Yin-Shan Yang ◽  
Karine de Guillen ◽  
Cécile Dubois ◽  
Catherine Anne Royer ◽  
...  
Keyword(s):  
High Pressure ◽  
Staphylococcal Nuclease ◽  
Comparative Assessment ◽  
Side Chain ◽  
Folding Pathway ◽  
Hydrophobic Core ◽  
Folding Pathways ◽  
Partial Unfolding ◽  
Protein Folding Pathways ◽  
Similar Description

Multidimensional NMR intrinsically provides multiple probes that can be used for deciphering the folding pathways of proteins: NH amide and CH groups are strategically located on the backbone of the protein, while CH3 groups, on the side-chain of methylated residues, are involved in important stabilizing interactions in the hydrophobic core. Combined with high hydrostatic pressure, these observables provide a powerful tool to explore the conformational landscapes of proteins. In the present study, we made a comparative assessment of the NH, CH, and CH3 groups for analyzing the unfolding pathway of ∆+PHS Staphylococcal Nuclease. These probes yield a similar description of the folding pathway, with virtually identical thermodynamic parameters for the unfolding reaction, despite some notable differences. Thus, if partial unfolding begins at identical pressure for these observables (especially in the case of backbone probes) and concerns similar regions of the molecule, the residues involved in contact losses are not necessarily the same. In addition, an unexpected slight shift toward higher pressure was observed in the sequence of the scenario of unfolding with CH when compared to amide groups.

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