Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

Malagrinò, Francesca; Visconti, Lorenzo; Pagano, Livia; Toto, Angelo; Troilo, Francesca; Gianni, Stefano

doi:10.3390/ijms21103484

Cited by 16 publications

(10 citation statements)

References 64 publications

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“…Such intrinsically disordered regions are common in eukaryotic proteins and important biological functions have been associated with them, such as flexible linker, cellular signal transduction, protein phosphorylation 108,109 . It has been observed that function can arise directly from the disordered state whereas in other cases their function originates from binding-induced folding promoted by other proteins or RNA, DNA molecules 110 . Evidence of EYA3 as an integrator of photoperiodic cues and nutritional regulation was recently found in Atlantic cod (Gadus morhua) 111 .…”

Section: Discussionmentioning

confidence: 99%

Non-synonymous variation and protein structure of candidate genes associated with selection in farm and wild populations of turbot (Scophthalmus maximus)

Andersen

Rubiolo

Pirolli³

et al. 2023

Sci Rep

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Non-synonymous variation (NSV) of protein coding genes represents raw material for selection to improve adaptation to the diverse environmental scenarios in wild and livestock populations. Many aquatic species face variations in temperature, salinity and biological factors throughout their distribution range that is reflected by the presence of allelic clines or local adaptation. The turbot (Scophthalmus maximus) is a flatfish of great commercial value with a flourishing aquaculture which has promoted the development of genomic resources. In this study, we developed the first atlas of NSVs in the turbot genome by resequencing 10 individuals from Northeast Atlantic Ocean. More than 50,000 NSVs where detected in the ~ 21,500 coding genes of the turbot genome, and we selected 18 NSVs to be genotyped using a single Mass ARRAY multiplex on 13 wild populations and three turbot farms. We detected signals of divergent selection on several genes related to growth, circadian rhythms, osmoregulation and oxygen binding in the different scenarios evaluated. Furthermore, we explored the impact of NSVs identified on the 3D structure and functional relationship of the correspondent proteins. In summary, our study provides a strategy to identify NSVs in species with consistently annotated and assembled genomes to ascertain their role in adaptation.

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Section: Discussionmentioning

confidence: 99%

Non-synonymous variation and protein structure of candidate genes associated with selection in farm and wild populations of turbot (Scophthalmus maximus)

Andersen

Rubiolo

Pirolli³

et al. 2023

Sci Rep

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show abstract

“…Φ-analysis has been applied successfully to the folding of transmembrane proteins (Otzen, 2011;Booth, 2012;Paslawski et al, 2015) and includes processes with receptors and gating (Cymes et al, 2002;Mitra et al, 2004;Cadugan and Auerbach, 2007;Aleksandrov et al, 2009;Edelstein and Changeux, 2010). Φ -analysis is particularly useful for studying the folding of intrinsically disordered proteins on binding to folded partners (Karlsson et al, 2012;Dogan et al, 2013Dogan et al, , 2014Rogers et al, 2014;Shammas et al, 2016;Karlsson et al, 2019;Toto et al, 2019;Karlsson et al, 2020;Malagrino et al, 2020;Toto et al, 2020;Karlsson and Jemth, 2021) and for proteins where mechanical force mimics their function in vivo Fowler et al, 2002). It has been extended to RNA folding (Silverman and Cech, 2001;Young and Silverman, 2002;Kim and Shin, 2010;Pereyaslavets and Galzitskaya, 2015) and DNA aptamers (Lawrence et al, 2014).…”

Section: Other Examples With φ-Valuesmentioning

confidence: 99%

From covalent transition states in chemistry to noncovalent in biology: from β- to Φ-value analysis of protein folding

Fersht

2024

Quart. Rev. Biophys.

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Solving the mechanism of a chemical reaction requires determining the structures of all the ground states on the pathway and the elusive transition states linking them. 2024 is the centenary of Brønsted’s landmark paper that introduced the β-value and structure-activity studies as the only experimental means to infer the structures of transition states. It involves making systematic small changes in the covalent structure of the reactants and analysing changes in activation and equilibrium-free energies. Protein engineering was introduced for an analogous procedure, Φ-value analysis, to analyse the noncovalent interactions in proteins central to biological chemistry. The methodology was developed first by analysing noncovalent interactions in transition states in enzyme catalysis. The mature procedure was then applied to study transition states in the pathway of protein folding – ‘part (b) of the protein folding problem’. This review describes the development of $ {\varPhi } $ -value analysis of transition states and compares and contrasts the interpretation of β- and Φ-values and their limitations. Φ-analysis afforded the first description of transition states in protein folding at the level of individual residues. It revealed the nucleation-condensation folding mechanism of protein domains with the transition state as an expanded, distorted native structure, containing little fully formed secondary structure but many weak tertiary interactions. A spectrum of transition states with various degrees of structural polarisation was then uncovered that spanned from nucleation-condensation to the framework mechanism of fully formed secondary structure. Φ-analysis revealed how movement of the expanded transition state on an energy landscape accommodates the transition from framework to nucleation-condensation mechanisms with a malleability of structure as a unifying feature of folding mechanisms. Such movement follows the rubric of analysis of classical covalent chemical mechanisms that began with Brønsted. Φ-values are used to benchmark computer simulation, and $ {\varPhi } $ and simulation combine to describe folding pathways at atomic resolution.

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“…Therefore, the binding process starts with docking of residues 25À41 of E3 to Im3; subsequently, E3 undergoes structure reorganization (disordered E3) or orientation rearrangement (ordered E3), allowing the N-terminal region to coalesce to the binding site (43). Experimentally, the binding mechanism and involvement of individual residue can be revealed from the f-value measurement (44). Because the tyrosine residue unfolding E3 is located within the hydrophobic core (27,45), it may be possible to carry out mutagenesis at the binding interface for ordered E3 and disordered E3 and measure the corresponding f-values.…”

Section: Binding Simulation Of E3 With Im3 Under the Transition Midpointmentioning

confidence: 99%

Introducing intrinsic disorder reduces electrostatic steering in protein-protein interactions

Gao

Han

Zeng

et al. 2021

Biophysical Journal

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Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

Cited by 16 publications

References 64 publications

Non-synonymous variation and protein structure of candidate genes associated with selection in farm and wild populations of turbot (Scophthalmus maximus)

Non-synonymous variation and protein structure of candidate genes associated with selection in farm and wild populations of turbot (Scophthalmus maximus)

From covalent transition states in chemistry to noncovalent in biology: from β- to Φ-value analysis of protein folding

Introducing intrinsic disorder reduces electrostatic steering in protein-protein interactions

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