Structure-based model of allostery predicts coupling between distant sites

Weinkam, Patrick; Pons, Jaume; Šali, Andrej

doi:10.1073/pnas.1116274109

Cited by 161 publications

(180 citation statements)

References 38 publications

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“…Only long range hydrogen bonds (that connected residues separated by more than 10 residues in the protein sequence) were considered in order to exclude interactions related to local secondary structures. Most of these hydrogen bonds were conserved along the MD trajectories, except for one hydrogen bond between Asn 35 360 or Arg 338 was modified to Ala. These observations show that the overall structure of the LHL motif is conserved in all systems and that the LHL connection to C-CaM on one side as well as to the C-loop on the other side were significantly weakened in the presence of the triple modification.…”

Section: Aspsupporting

confidence: 50%

Allosteric Activation of Bordetella pertussis Adenylyl Cyclase by Calmodulin

Selwa

Davi

Chenal

et al. 2014

Journal of Biological Chemistry

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Background: Adenylyl cyclase (AC) from Bordetella pertussis is activated when it interacts with calmodulin (CaM). Results: A triple mutant of AC, which was predicted by molecular modeling, exhibited a highly reduced affinity for CaM. Conclusion: This study suggests that a long range connection between CaM and the AC catalytic loop is crucial for AC activation. Significance: Molecular modeling identified critical molecular determinants for the allosteric activation of AC.

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Section: Aspsupporting

confidence: 50%

Allosteric Activation of Bordetella pertussis Adenylyl Cyclase by Calmodulin

Selwa

Davi

Chenal

et al. 2014

Journal of Biological Chemistry

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“…Single-state model of the pASK1-CD⅐14-3-3 complex. A, the best-scoring single-state model of the pASK1-CD⅐14-3-3 complex calculated using the AllosMod-FoXS server (22,23). The 14-3-3 is shown in brown, and ASK1-CD is shown in cyan (each protomer is shown in a different shade).…”

Section: Discussionmentioning

confidence: 99%

“…Structural Modeling of the pASK1-CD⅐14-3-3 Complex Using SAXS and Cross-linking Data-The AllosMod-FoXS web server was used to prepare models of ASK1-CD and the ASK1-CD⅐14-3-3 complex as well as to generate their alternate conformations consistent with the experimental SAXS data (22,23). The model of ASK1-CD (659 -973) was prepared using the crystal structure of the kinase domain of ASK1 (670 -940) (48).…”

Section: Methodsmentioning

confidence: 99%

“…All-Atom Modeling of the pASK1-CD⅐14-3-3⌬C ComplexThe all-atom modeling of the pASK1-CD⅐14-3-3⌬C complex was first performed using the AllosMod-FoXS method (22,23). The best-scoring single-state AllosMod model fits the SAXS data with ϭ 1.66 and shows the C-lobe of one protomer of ASK1-CD interacting with ␣-helices H4 and H6 of 14-3-3 outside its central channel through a relatively small binding interface (Fig.…”

Section: Biophysical Characterization Of the Pask1-cd⅐14-3-3mentioning

confidence: 99%

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Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)

Petrvalská

Košek

Kukačka

et al. 2016

Journal of Biological Chemistry

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Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, regulates diverse physiological processes. The activity of ASK1 is triggered by various stress stimuli and is involved in the pathogenesis of cancer, neurodegeneration, inflammation, and diabetes. ASK1 forms a high molecular mass complex whose activity is, under non-stress conditions, suppressed through interaction with thioredoxin and the scaffolding protein 14-3-3. The 14-3-3 protein binds to the phosphorylated Ser-966 motif downstream of the ASK1 kinase domain. The role of 14-3-3 in the inhibition of ASK1 has yet to be elucidated. In this study we performed structural analysis of the complex between the ASK1 kinase domain phosphorylated at Ser-966 (pASK1-CD) and the 14-3-3 protein. Small angle x-ray scattering (SAXS) measurements and chemical cross-linking revealed that the pASK1-CD⅐14-3-3 complex is dynamic and conformationally heterogeneous. In addition, structural analysis coupled with the results of phosphorus NMR and time-resolved tryptophan fluorescence measurements suggest that 14-3-3 interacts with the kinase domain of ASK1 in close proximity to its active site, thus indicating this interaction might block its accessibility and/or affect its conformation.

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“…Functional change results from changes in the protein energy landscape elicited by ligand binding (4). This change in energy landscape may lead to conformational change and/or may be more subtly expressed as a change in protein molecular dynamics (5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

Cross

Allison

Dobson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Allosteric regulation of protein function is a critical component of metabolic control. Its importance is underpinned by the diversity of mechanisms and its presence in all three domains of life. The first enzyme of the aromatic amino acid biosynthesis, 3-deoxy-Darabino-heptulosonate 7-phosphate synthase, shows remarkable variation in allosteric response and machinery, and both contemporary regulated and unregulated orthologs have been described. To examine the molecular events by which allostery can evolve, we have generated a chimeric protein by joining the catalytic domain of an unregulated 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with the regulatory domain of a regulated enzyme. We demonstrate that this simple gene fusion event on its own is sufficient to confer functional allostery to the unregulated enzyme. The fusion protein shares structural similarities with its regulated parent protein and undergoes an analogous major conformational change in response to the binding of allosteric effector tyrosine to the regulatory domain. These findings help delineate a remarkably facile mechanism for the evolution of modular allostery by domain recruitment.ACT domain | shikimate P rotein allostery, where ligand binding is coupled to a functional change at a remote site, is critical for the control of metabolism. For enzymes of key metabolic pathways, allostery allows precise control of catalysis in response to cellular demand. Although this important phenomenon was first described many years ago, it is only more recently that the molecular details that govern this precise control of enzyme function have been explored for a diverse range of protein systems (1-3). Functional change results from changes in the protein energy landscape elicited by ligand binding (4). This change in energy landscape may lead to conformational change and/or may be more subtly expressed as a change in protein molecular dynamics (5-12).The importance of protein allostery is underpinned by the observation that it is ubiquitous. As more proteins are studied in detail, one of the striking revelations is the variety of allosteric mechanisms that are used to control protein function. These mechanisms can be broadly divided into three groups that reflect the evolutionary path taken to acquire the allosteric functionality (5). In the first group, modification of existing structural features of a protein creates an allosteric site. Second, the formation of homo-and heterooligomeric assemblies may lead to the development of allosteric sites at the interface of subunits. Third, allostery may be endowed by domain fusion to create a modular protein with a distinct domain responsible for binding of the allosteric effector. A detailed understanding of this modular allostery, in which the allosteric effector binding site is associated with a discrete protein domain, offers the potential to generate engineered proteins with tailored functionality.The ACT domain has been identified as a modular regulatory unit associated with the control of a var...

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Structure-based model of allostery predicts coupling between distant sites

Cited by 161 publications

References 38 publications

Allosteric Activation of Bordetella pertussis Adenylyl Cyclase by Calmodulin

Allosteric Activation of Bordetella pertussis Adenylyl Cyclase by Calmodulin

Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

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