Specific and Fuzzy Interactions Cooperate in Modulating Protein Half-Life

Demény, Máté Ágoston; Ambrus, Viktor; Király, Sándor Balázs; Kurtán, Tibor; Gatti‐Lafranconi, Pietro; Fuxreiter, Mónika

doi:10.1016/j.jmb.2019.02.006

Cited by 4 publications

(5 citation statements)

References 65 publications

(86 reference statements)

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“…Given that the aromatic cage‐mediated K/Rme recognition mechanism of readers in living cells can be probed by using cage residue mutants, the conclusions (i.e., loss of binding for reader mutants) of such live‐cell experiments might have been partly due to compromised stability. This argument is based on the observation of enhanced degradation (i.e., shorter half‐lives) of stability‐compromised mutants in cells (Sharma et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Assessing the functional roles of coevolving PHD finger residues

Basu,

Subedi,

Tonelli

et al. 2024

Protein Science

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Although in silico folding based on coevolving residue constraints in the deep‐learning era has transformed protein structure prediction, the contributions of coevolving residues to protein folding, stability, and other functions in physical contexts remain to be clarified and experimentally validated. Herein, the PHD finger module, a well‐known histone reader with distinct subtypes containing subtype‐specific coevolving residues, was used as a model to experimentally assess the contributions of coevolving residues and to clarify their specific roles. The results of the assessment, including proteolysis and thermal unfolding of wildtype and mutant proteins, suggested that coevolving residues have varying contributions, despite their large in silico constraints. Residue positions with large constraints were found to contribute to stability in one subtype but not others. Computational sequence design and generative model‐based energy estimates of individual structures were also implemented to complement the experimental assessment. Sequence design and energy estimates distinguish coevolving residues that contribute to folding from those that do not. The results of proteolytic analysis of mutations at positions contributing to folding were consistent with those suggested by sequence design and energy estimation. Thus, we report a comprehensive assessment of the contributions of coevolving residues, as well as a strategy based on a combination of approaches that should enable detailed understanding of the residue contributions in other large protein families.

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Section: Discussionmentioning

confidence: 99%

Assessing the functional roles of coevolving PHD finger residues

Basu,

Subedi,

Tonelli

et al. 2024

Protein Science

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“…In addition, molecular docking results predicted a stretch of amino acids from AGL15 interacting with BBM1. A higher number of hydrophobic amino acids at the interface in the complexes BBM-frag2: LEC1 and BBM-frag2: AGLI5-frag1resonate the concept that non-polar (or hydrophobic) residues predominantly occur at the protein interface, playing a major role in contributing to the driving force for binding [ 48 ]. Further, the protein interaction mediating the K-domain of AGAMOUS (AG) is known to contain three hydrophobic alpha helices, which are conserved across its interacting partners like MADS, LEC1, and LEA, key regulators of embryogenesis [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

BabyBoom: 3-Dimensional Structure-Based Ligand and Protein Interaction Prediction by Molecular Docking

Panchangam¹

2022

Biomolecules

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Baby Boom (BBM) is a key transcription factor that triggers embryogenesis, enhances transformation and regeneration efficiencies, and regulates developmental pathways in plants. Triggering or activating BBM in non-model crops could overcome the bottlenecks in plant breeding. Understanding BBM’s structure is critical for functional characterization and determination of interacting partners and/or ligands. The current in silico study aimed to study BBM’s sequence and conservation across all plant proteomes, predict protein-protein and protein-ligand interactions, and perform molecular docking and molecular dynamics (MD) simulation to specifically determine the binding site amino acid residues. In addition, peptide sequences that interact with BBM have also been predicted, which provide avenues for altered functional interactions and the design of peptide mimetics that can be experimentally validated for their role in tissue culture or transformation media. This novel data could pave the way for the exploitation of BBM’s potential as the master regulator of specialized plant processes such as apomixes, haploid embryogenesis, and CRISPR/Cas9 transgenic development.

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“…While the phrase coupled binding and folding is quite frequently used while discussing protein functionality, it is important to keep in mind that even "folding" is best described as a part of continuum, in which the disorder of the protein is retained in the complex in a wide range with "fuzzy complexes" as one extreme end of the spectrum (Chowdhury et al, 2023;Freiberger et al, 2021;Fuxreiter, 2012Fuxreiter, , 2018Fuxreiter, , 2019Fuxreiter, , 2020Fuxreiter & Tompa, 2012;Gruet et al, 2016;Miskei et al, 2020Miskei et al, , 2017Sharma et al, 2015Sharma et al, , 2019Tompa & Fuxreiter, 2008;Welch, 2012). A recent review by Chowdhury et al comprehensively covers the insights on protein-protein interactions (involving IDPs/IDRs) from the single molecule Förster resonance energy transfer (FRET, also known as fluorescence resonance energy transfer) (Chowdhury et al, 2023).…”

Section: Interactions Of Idps/idrs With Other Proteins and Surfaces I...mentioning

confidence: 99%

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Gupta,

Uversky

2024

Protein Science

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The rationale for replacing the old binary of structure–function with the trinity of structure, disorder, and function has gained considerable ground in recent years. A continuum model based on the expanded form of the existing paradigm can now subsume importance of both conformational flexibility and intrinsic disorder in protein function. The disorder is actually critical for understanding the protein–protein interactions in many regulatory processes, formation of membrane‐less organelles, and our revised notions of specificity as amply illustrated by moonlighting proteins. While its importance in formation of amyloids and function of prions is often discussed, the roles of intrinsic disorder in infectious diseases and protein function under extreme conditions are also becoming clear. This review is an attempt to discuss how our current understanding of protein function, specificity, and evolution fit better with the continuum model. This integration of structure and disorder under a single model may bring greater clarity in our continuing quest for understanding proteins and molecular mechanisms of their functionality.

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Specific and Fuzzy Interactions Cooperate in Modulating Protein Half-Life

Cited by 4 publications

References 65 publications

Assessing the functional roles of coevolving PHD finger residues

Assessing the functional roles of coevolving PHD finger residues

BabyBoom: 3-Dimensional Structure-Based Ligand and Protein Interaction Prediction by Molecular Docking

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

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