Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1
Open accessAbstract
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 αC 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.
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Yan et al. used molecular dynamics simulations to show that peptide binding causes interdomain motions in the A-loop.
“These conclusions are supported by the findings of Yan et al., who showed utilizing molecular dynamic simulations that peptide binding caused interdomain motions in the A-loop (Yan et al., 2011).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Yan et al., 2011
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Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases
Laughlin, J. D., Nwachukwu, J. C., Figuera-Losada, M., Cherry, L., Nettles, K. W., & LoGrasso, P. V. (2012) · Structure · doi:10.1016/j.str.2012.09.021 · Cited by 50 · see citing works
“These conclusions are supported by the findings of Yan et al., who showed utilizing molecular dynamic simulations that peptide binding caused interdomain motions in the A-loop (Yan et al., 2011).”
BackgroundResult
- Authors
- Yan, C., Kaoud, T., Lee, S., Dalby, K. N., & Ren, P.
- Affiliations
- The University of Texas at Austin (US)
- Corresponding author
- Dalby, Kevin N.
- Ren, Pengyu
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-01-25
- Volume
- 115
- Issue
- 6
- Pages
- 1491-1502
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- PMC
- PMC3042137
- OpenAlex
- W1972788136
- Cited by
- 36
- References
- 83
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 4 · 2012: 11
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physical Chemistry B (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM059802, R01GM079686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- JNK1, JIP1, protein-peptide docking, allosteric regulation, activation loop, interdomain motion, binding free energy, electrostatic interactions, binding specificity, JNK inhibition, essential dynamics, alanine scanning, MAPK signaling
- MeSH terms
- Allosteric Regulation, Humans, Mutation, Protein Binding, Thermodynamics, Protein Structure, Tertiary, Amino Acid Substitution, Mitogen-Activated Protein Kinase 1, Catalytic Domain, Mitogen-Activated Protein Kinase 8, Adaptor Proteins, Signal Transducing, Molecular Dynamics Simulation
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