Linked Life Data

21261310

Source:http://linkedlifedata.com/resource/pubmed/id/21261310

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2011-2-10
pubmed:abstractText
The up-regulation of JNK activity is associated with a number of disease states. The JNK-JIP1 interaction represents an attractive target for the inhibition of JNK-mediated signaling. In this study, molecular dynamics simulations have been performed on the apo-JNK1 and the JNK1•L-pepJIP1 and JNK1•D-pepJIP1 complexes to investigate the interaction between the JIP1 peptides and JNK1. Dynamic domain studies based on essential dynamics (ED) analysis of apo-JNK1 and the JNK1•L-pepJIP1 complex have been performed to analyze and compare details of conformational changes, hinge axes, and hinge bending regions in both structures. The activation loop, the ?C helix, and the G loop are found to be highly flexible and to exhibit significant changes in dynamics upon L-pepJIP1 binding. The conformation of the activation loop for the apo state is similar to that of inactive apo-ERK2, while the activation loop in JNK1•L-pepJIP1 complex resembles that of the inactive ERK2 bound with pepHePTP. ED analysis shows that, after the binding of l-pepJIP1, the N- and C-terminal domains of JNK1 display both a closure and a twisting motion centered around the activation loop, which functions as a hinge. In contrast, no domain motion is detected for the apo state for which an open conformation is favored. The present study suggests that L-pepJIP1 regulates the interdomain motions of JNK1 and potentially the active site via an allosteric mechanism. The binding free energies of L-pepJIP1 and D-pepJIP1 to JNK1 are estimated using the molecular mechanics Poisson-Boltzmann and generalized-Born surface area (MM-PB/GBSA) methods. The contribution of each residue at the interaction interface to the binding affinity of L-pepJIP1 with JNK1 has been analyzed by means of computational alanine-scanning mutagenesis and free energy decomposition. Several critical interactions for binding (e.g., Arg156/L-pepJIP1 and Glu329/JNK1) have been identified. The binding free energy calculation indicates that the electrostatic interaction contributes critically to specificity, rather than to binding affinity between the peptide and JNK1. Notably, the binding free energy calculations predict that D-pepJIP1 binding to JNK1 is significantly weaker than the L form, contradicting the previous suggestion that D-pepJIP1 acts as an inhibitor toward JNK1. We have performed experiments using purified JNK1 to confirm that, indeed, D-pepJIP1 does not inhibit the ability of JNK1 to phosphorylate c-Jun in vitro.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1520-5207
pubmed:author
pubmed:issnType
Electronic
pubmed:day
17
pubmed:volume
115
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1491-502
pubmed:dateRevised
2011-6-10
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1.
pubmed:affiliation
Department of Biomedical Engineering, University of Texas, Austin, Texas 78712, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural