Exploitation of Latent Allostery Enables the Evolution of New Modes of MAP Kinase Regulation

Coyle, Scott M.; Flores, Jonathan; Lim, Wendell A.

doi:10.1016/j.cell.2013.07.019

Cited by 56 publications

(91 citation statements)

References 38 publications

(51 reference statements)

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“…The mechanism of such binding may lie anywhere between the 'conformational selection' and 'induced fit' scenarios [177,200]. Evolution has apparently exploited latent allosteric potentials entailed by conformational dynamics in this manner, as in the case of Ste5 activators that target MAP kinases in yeast [201].…”

Section: Conformational Diversity Is Often Needed For Functionmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

220

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Conformational Diversity Is Often Needed For Functionmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

220

207

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“…This mechanism has been shown to allosterically increase the affinity of p38␣ for ATP. The second example of a structurally defined MAPK-binding protein interaction that triggers activation loop autophosphorylation is the yeast Ste5-Fus3 interaction (6,33). While the cis autophosphorylation of Fus3's activation loop Y is activated by the binding of a segment from Ste5, this interaction does not appear to increase Fus3's affinity for ATP.…”

Section: Discussionmentioning

confidence: 99%

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

Tio

Omerza

Phillips

et al. 2017

Molecular and Cellular Biology

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Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in Saccharomyces cerevisiae that couples spore morphogenesis to the completion of chromosome segregation. Similar to other MAPKs, Smk1 is controlled by phosphorylation of a threonine (T) and a tyrosine (Y) in its activation loop. However, it is not activated by a dual-specificity MAPK kinase. Instead, T207 in Smk1's activation loop is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase (Cak1), and Y209 is autophosphorylated in an intramolecular reaction that requires the meiosis-specific protein Ssp2. In this study, we show that Smk1 is catalytically inert unless it is bound by Ssp2. While Ssp2 binding activates Smk1 by a mechanism that is independent of activation loop phosphorylation, binding also triggers autophosphorylation of Y209 in Smk1, which, along with Cak1-mediated phosphorylation of T207, further activates the kinase. Autophosphorylation of Smk1 on Y209 also appears to modify the specificity of the MAPK by suppressing Y kinase and enhancing S/T kinase activity. We also found that the phosphoconsensus motif preference of Ssp2/Smk1 is more extensive than that of other characterized MAPKs. This study therefore defines a novel mechanism of MAPK activation requiring binding of an activator and also shows that MAPKs can be diversified to recognize unique phosphorylation motifs.

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“…In budding yeast ( S. cerevisiae ) two allosteric activators (effectors) within the scaffold protein Ste5 regulate the MAP kinase Fus3 (Coyle et al, 2013). Surprisingly, when tested in vitro , these activators also regulate evolutionarily distant MAP kinases – kinases present in fungal species that diverged prior to the evolution of a Ste5 scaffold protein.…”

Section: Allosteric Regulation – a Short Introductionmentioning

confidence: 99%

An evolution-based strategy for engineering allosteric regulation

2017

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Allosteric regulation provides a way to control protein activity at the time scale of milliseconds to seconds inside the cell. An ability to engineer synthetic allosteric systems would be of practical utility for the development of novel biosensors, creation of synthetic cell signaling pathways, and design of small molecule pharmaceuticals with regulatory impact. To this end, we outline a general approach – termed Rational Engineering of Allostery at Conserved Hotspots (REACH) – to introduce novel regulation into a protein of interest by exploiting latent allostery that has been hard-wired by evolution into its structure. REACH entails the use of statistical coupling analysis (SCA) to identify “allosteric hotspots” on protein surfaces, the development and implementation of experimental assays to test hotspots for functionality, and a toolkit of allosteric modulators to impinge on endogenous cellular circuitry. REACH can be broadly applied to rewire cellular processes to respond to novel inputs.

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Exploitation of Latent Allostery Enables the Evolution of New Modes of MAP Kinase Regulation

Cited by 56 publications

References 38 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

An evolution-based strategy for engineering allosteric regulation

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