Frustration Sculpts the Early Stages of Protein Folding

Silvio, Eva Di; Brunori, Maurizio; Gianni, Stefano

doi:10.1002/anie.201504835

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…Frustration in biological systems has also been invoked to understand the folding energy landscape of proteins, 81−83 where individual local molecular arrangements that minimize energy may be mutually incompatible, resulting in rugged energy landscapes and misfolded states. Other systems that may exhibit some frustration include gene expression networks, 84 morphological innovation, 85 and even the evolution of biological complexity.…”

Section: Discussionmentioning

confidence: 99%

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA

et al. 2019

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Molecular evolution can be conceptualized as a walk over a “fitness landscape”, or the function of fitness (e.g., catalytic activity) over the space of all possible sequences. Understanding evolution requires knowing the structure of the fitness landscape and identifying the viable evolutionary pathways through the landscape. However, the fitness landscape for any catalytic biomolecule is largely unknown. The evolution of catalytic RNA is of special interest because RNA is believed to have been foundational to early life. In particular, an essential activity leading to the genetic code would be the reaction of ribozymes with activated amino acids, such as 5(4H)-oxazolones, to form aminoacyl-RNA. Here we combine in vitro selection with a massively parallel kinetic assay to map a fitness landscape for self-aminoacylating RNA, with nearly complete coverage of sequence space in a central 21-nucleotide region. The method (SCAPE: sequencing to measure catalytic activity paired with in vitro evolution) shows that the landscape contains three major ribozyme families (landscape peaks). An analysis of evolutionary pathways shows that, while local optimization within a ribozyme family would be possible, optimization of activity over the entire landscape would be frustrated by large valleys of low activity. The sequence motifs associated with each peak represent different solutions to the problem of catalysis, so the inability to traverse the landscape globally corresponds to an inability to restructure the ribozyme without losing activity. The frustrated nature of the evolutionary network suggests that chance emergence of a ribozyme motif would be more important than optimization by natural selection.

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Section: Discussionmentioning

confidence: 99%

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA

et al. 2019

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“…However, the second transition state (from the intermediate to the native state) was similar to that found for the wild-type. Hence, TS1 has been revealed to be more malleable than TS2 [21]. As a consequence, altering the topology or the sequence of PTP-BL PDZ2 produces a TS2 with more similar structures between the variants.…”

Section: Pdz Folding and Implications In The Folding Mechanism Theoriesmentioning

confidence: 99%

The Conformational Plasticity Vista of PDZ Domains

Murciano-Calles

2020

Life

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The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in this domain family, based just on a static perspective of the structure–activity relationship, might fall short. More dynamic and conformational aspects in the protein fold can be the reasons for such functionality. Folding studies indeed showed an ample and malleable folding landscape for PDZ domains where multiple intermediate states were experimentally detected. Allosteric phenomena that resemble energetic coupling between residues have also been found in PDZ domains. Additionally, several PDZ domains are modulated by post-translational modifications, which introduce conformational switches that affect binding. Altogether, the ability to connect diverse partners might arise from the intrinsic plasticity of the PDZ fold.

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“…The energy landscape theory proposes that proteins, while marginally stable, are strongly biased toward their native structure, which is therefore minimally frustrated . Because of the contrasting demands of folding and function, however, it is plausible to assume that the functionally competent site(s) of a protein may contain a certain level of local frustration, such that, in those regions, the sequence is not necessarily optimized to fold. , The presence of these patterns may lead to local misfolding, which may reveal itself in the early events of folding. , By following this hypothesis, it is of interest to localize on the three-dimensional structure of native KIX the sites of mutations associated in a relevant increase of m D–N value ( i.e. , the mutants whose m value is at least 0.1 kcal mol –1 M –1 higher than that of the wild type; Figure ).…”

Section: Discussionmentioning

confidence: 99%

The Folding Pathway of the KIX Domain

et al. 2017

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The KIX domain is an 89-residues globular domain with an important role in mediating protein-protein interactions. The presence of two distinct binding sites in such a small domain makes KIX a suitable candidate to investigate the effect of the potentially divergent demands between folding and function. Here, we report an extensive mutational analysis of the folding pathway of the KIX domain, based on 30 site-directed mutants, which allow us to assess the structures of both the transition and denatured states. Data reveal that, while the transition state presents mostly native-like interactions, the denatured state is somewhat misfolded. We mapped some of the non-native contacts in the denatured state using a second round of mutagenesis, based on double mutant cycles on 15 double mutants. Interestingly, such a misfolding arises from non-native interactions involving the residues critical for the function of the protein. The results described in this work appear to highlight the diverging demands between folding and function that may lead to misfolding, which may be observed in the early stages of folding.

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Frustration Sculpts the Early Stages of Protein Folding

Cited by 13 publications

References 22 publications

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA

The Conformational Plasticity Vista of PDZ Domains

The Folding Pathway of the KIX Domain

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