Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Yang, Jing; Gao, Meng; Xiong, Junwen; Su, Zhengding; Huang, Yongqi

doi:10.1002/pro.3718

Cited by 65 publications

(55 citation statements)

References 206 publications

(442 reference statements)

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“…Another example is the mutually induced conformational change in both calmodulin and its target proteins, which is required to achieve both high affinity and high specificity 39 . On the other hand, in intrinsically-disordered proteins (IDPs), which bind structured partner molecules, the induced-folding, or folding-upon-binding, mechanism is dominant 40,41 , but combined conformational selection with folding-upon-binding was found to direct the redox switch CP12 42 . In IDPs that do not form ordered complex structures, a fuzzy-complex-formation mechanism is also observed, e.g.…”

Section: Discussionmentioning

confidence: 99%

Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations

Bekker

Fukuda

Higo

et al. 2020

Sci Rep

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Antibody based bio-molecular drugs are an exciting, new avenue of drug development as an alternative to the more traditional small chemical compounds. However, the binding mechanism and the effect on the conformational ensembles of a therapeutic antibody to its peptide or protein antigen have not yet been well studied. We have utilized dynamic docking and path sampling simulations based on allatom molecular dynamics to study the binding mechanism between the antibody solanezumab and the peptide amyloid-β (Aβ). our docking simulations reproduced the experimental structure and gave us representative binding pathways, from which we accurately estimated the binding free energy. not only do our results show why solanezumab has an explicit preference to bind to the monomeric form of Aβ, but that upon binding, both molecules are stabilized towards a specific conformation, suggesting that their complex formation follows a novel, mutual population-shift model, where upon binding, both molecules impact the dynamics of their reciprocal one. With pathogen targeting antibodies being one of the key treatments in immunotherapy 1,2 , molecular recognition of an antibody to its antigen proteins or peptides has attracted great attention 3. Understanding the recognition mechanism provides crucial information for rational design of an antibody 4 , which could potentially be attained by studying the native binding configuration at atomistic resolution. Although X-ray crystallography is a powerful tool, the binding mechanism cannot be elucidated, as it is not possible to investigate the binding process via intermediary structures. In contrast, while molecular dynamics (MD) simulations offer the possibility to investigate the binding mechanism by studying the entire conformational space, they cannot reach the timescales that biologically interesting phenomena occur at. Enhanced MD simulation techniques such as multicanonical MD (McMD) 5-14 accelerate the dynamics while having the innate ability to re-obtain the canonical ensemble at a given temperature. This enables us to study phenomena such as the binding between molecules at atomistic resolution, not offered by either experimental methods or conventional MD simulations. Recently, docking using advanced MD, such as McMD, Replica Exchange MD 15 , Filling Potential 16 , Metadynamics 17 , Accelerated MD 18 and even Markov State Modelling of MD simulations 19 , has attracted much attention in the field of protein-drug interaction, where such methods have been coined dynamic docking 20. Currently, three basic models exist for the molecular recognition by antibodies; lock-and-key, conformational selection and induced fit 21-26. In the lock-and-key model, no conformational change of the antibody is required for the antigen to bind. On the other hand, for the conformational selection model, also known as the population-shift model, the two molecules only bind when the antibody is in a bound-like conformation before attempting to bind, leading to a population-shift. Finally, in the induced fi...

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Section: Discussionmentioning

confidence: 99%

Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations

Bekker

Fukuda

Higo

et al. 2020

Sci Rep

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“…It is commonly accepted that IDRs are enriched in proteins involved in signaling and regulatory functions (see ref. [ 37 ] and references therein) and that they are able to mediate functional protein-protein interactions. This is often done by molecular recognition features (MoRFs) or short linear motifs, which usually undergo disorder-to-order transitions upon binding to their partners.…”

Section: Discussionmentioning

confidence: 99%

The N-Terminal Region of Yeast Protein Phosphatase Ppz1 Is a Determinant for Its Toxicity

Calafí

López-Malo

Albacar

et al. 2020

IJMS

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The Ppz enzymes are Ser/Thr protein phosphatases present only in fungi that are characterized by a highly conserved C-terminal catalytic region, related to PP1c phosphatases, and a more divergent N-terminal extension. In Saccharomyces cerevisiae, Ppz phosphatases are encoded by two paralog genes, PPZ1 and PPZ2. Ppz1 is the most toxic protein when overexpressed in budding yeast, halting cell proliferation, and this effect requires its phosphatase activity. We show here that, in spite of their conserved catalytic domain, Ppz2 was not toxic when tested under the same conditions as Ppz1, albeit Ppz2 levels were somewhat lower. Remarkably, a hybrid protein composed of the N-terminal extension of Ppz1 and the catalytic domain of Ppz2 was as toxic as Ppz1, even if its expression level was comparable to that of Ppz2. Similar amounts of yeast PP1c (Glc7) produced an intermediate effect on growth. Mutation of the Ppz1 myristoylable Gly2 to Ala avoided the localization of the phosphatase at the cell periphery but only slightly attenuated its toxicity. Therefore, the N-terminal extension of Ppz1 plays a key role in defining Ppz1 toxicity. This region is predicted to be intrinsically disordered and contains several putative folding-upon-binding regions which are absent in Ppz2 and might be relevant for toxicity.

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“…Thus, PTMs allow IDPs to function in rheostatic regulation [17] which are graded quantitative responses, and may also drive the formation or disruption of membrane-less organelles through processes known as liquid-liquid phase separation (LLPS) [18,19]. Finally, the disordered nature of IDPs allows them to exploit diverse binding mechanisms by which they can fold-upon-binding [20][21][22], but also form complexes in which structural disorder is maintained to different degrees [23]. Here, the most extreme case is the formation of a completely disordered complex of functional relevance and extreme affinity [24].…”

Section: Introductionmentioning

confidence: 99%

Orchestration of signaling by structural disorder in class 1 cytokine receptors

et al. 2020

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Background: Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood. Methods: The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family. Results: We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions. Conclusions: Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential.

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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Cited by 65 publications

References 206 publications

Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations

Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations

The N-Terminal Region of Yeast Protein Phosphatase Ppz1 Is a Determinant for Its Toxicity

Orchestration of signaling by structural disorder in class 1 cytokine receptors

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