Experimental and molecular dynamics studies showed that CBP KIX mutation affects the stability of CBP:c-Myb complex

Odoux, Anne; Jindal, Darren; Tamas, Tamara C.; Lim, Benjamin; Pollard, D. R.; Xu, Wu

doi:10.1016/j.compbiolchem.2016.03.004

Cited by 10 publications

(12 citation statements)

References 72 publications

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“…For example, high concentrations will favor conformation selection over induced fit for kinetic reasons (65, 66). Currently, the majority of Φ -value analyses (30, 31, 34, 35, 67, 68) and simulation studies (69, 70, 71) also observe a relatively unstructured transition state for the interaction of IDPs with their partners, and most propose a (largely) induced fit mechanism where the majority of folding occurs after the rate-limiting binding step.…”

Section: Discussionmentioning

confidence: 99%

pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions

Dahal

Kwan

Shammas

et al. 2017

Biophysical Journal

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Understanding the detailed mechanism of interaction of intrinsically disordered proteins with their partners is crucial to comprehend their functions in signaling and transcription. Through its interaction with KIX, the disordered pKID region of CREB protein is central in the transcription of cAMP responsive genes, including those involved in long-term memory. Numerous simulation studies have investigated these interactions. Combined with experimental results, these can provide valuable and comprehensive understanding of the mechanisms involved. Here, we probe the transition state of this interaction experimentally through analyzing the kinetic effect of mutating both interface and solvent exposed residues in pKID. We show that very few specific interactions between pKID and KIX are required in the initial binding process. Only a small number of weak interactions are formed at the transition state, including nonnative interactions, and most of the folding occurs after the initial binding event. These properties are consistent with computational results and also the majority of experimental studies of intrinsically disordered protein coupled folding and binding in other protein systems, suggesting that these may be common features.

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Section: Discussionmentioning

confidence: 99%

pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions

Dahal

Kwan

Shammas

et al. 2017

Biophysical Journal

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“…More detailed investigations focusing on the molecular details of TAD-coactivator interactions identified common principles, such as the induction/stabilization of local α-helical structures and the functional importance of large hydrophobic side chains (for example [ 7 , 12 , 13 , 14 , 16 , 21 , 39 , 51 , 52 , 53 ]). Rather gratifyingly, despite the challenges of combining the simulation of intrinsically disordered TADs with more stably structured coactivators within a single model, atomistic molecular dynamics simulations of coactivator TAD complexes generally match the experimental facts well and are thus potentially capable of offering valid insights into questions that are not easily experimentally accessible [ 14 , 54 , 55 , 56 ]. Furthermore, computational models not only offer insights into the structural properties of ‘fuzzy complexes’, but also uncover energetic aspects of the highly dynamic binding events that confirm the key functional role of certain hydrophobic residues ( Figure 4 and Figure 5 ) [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

Jeffery

Weinzierl

2020

Biomolecules

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The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to refine further by experimental means. Here, we apply computational molecular dynamics simulations to study the interactions of two different TADs from the human transcription factor ETV5 (ERM) and herpes virus VP16-H1 with MED25. Like other well-studied coactivator-TAD complexes, the interactions of these intrinsically disordered domains with the coactivator surface are temporary and highly dynamic (‘fuzzy’). Due to the fact that the MED25 TAD-binding region is organized as an elongated cleft, we specifically asked whether these TADs are capable of binding in either orientation and how this could be achieved structurally and energetically. The binding of both the ETV5 and VP16-TADs in either orientation appears to be possible but occurs in a conformationally distinct manner and utilizes different sets of hydrophobic residues present in the TADs to drive the interactions. We propose that MED25 and at least a subset of human TADs specifically evolved a redundant set of molecular interaction patterns to allow binding to particular coactivators without major prior spatial constraints.

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“…The molecular modeling procedure was based on the methods described previously [ 26 , 41 ]. The sequences were aligned using the ClustalW pairwise alignment algorithm of the Vector NTI software (Life Technologies Corporation, Carlsbad, CA, USA) [ 42 ].…”

Section: Methodsmentioning

confidence: 99%

All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site

Xie

Faust

et al. 2020

IJMS

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Cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) play conserved roles in modulating RNA polymerase II (Pol II)-dependent gene expression. To understand the structure and function relations of CDK8, we analyzed the structures of human and Drosophila CDK8 proteins using molecular dynamics simulations, combined with functional analyses in Drosophila. Specifically, we evaluated the structural differences between hCDK8 and dCDK8 to predict the effects of the LXXLL motif mutation (AQKAA), the P154L mutations, and drug binding on local structures of the CDK8 proteins. First, we have observed that both the LXXLL motif and the kinase activity of CDK8 are required for the normal larval-to-pupal transition in Drosophila. Second, our molecular dynamic analyses have revealed that hCDK8 has higher hydrogen bond occupation of His149-Asp151 and Asp151-Asn156 than dCDK8. Third, the substructure of Asp282, Phe283, Arg285, Thr287 and Cys291 can distinguish human and Drosophila CDK8 structures. In addition, there are two hydrogen bonds in the LXXLL motif: a lower occupation between L312 and L315, and a relatively higher occupation between L312 and L316. Human CDK8 has higher hydrogen bond occupation between L312 and L316 than dCDK8. Moreover, L312, L315 and L316 in the LXXLL motif of CDK8 have the specific pattern of hydrogen bonds and geometries, which could be crucial for the binding to nuclear receptors. Furthermore, the P154L mutation dramatically decreases the hydrogen bond between L312 and L315 in hCDK8, but not in dCDK8. The mutations of P154L and AQKAA modestly alter the local structures around residues 154. Finally, we identified the inhibitor-induced conformational changes of hCDK8, and our results suggest a structural difference in the drug-binding site between hCDK8 and dCDK8. Taken together, these results provide the structural insights into the roles of the LXXLL motif and the kinase activity of CDK8 in vivo.

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Experimental and molecular dynamics studies showed that CBP KIX mutation affects the stability of CBP:c-Myb complex

Cited by 10 publications

References 72 publications

pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions

pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions

Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site

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