ArticleBriefings in bioinformatics2024
A novel approach to study multi-domain motions in JAK1's activation mechanism based on energy landscape.
Article in Briefings in bioinformatics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 12 citations in OpenAlex.
- Synergistic Interplay of Stimulatory Cofactors in the Activation of Adenylyl Cyclase Isoform 1.The journal of physical chemistry. B · 2025Article
- Local microenvironments of capsomer variants in the PBCV-1.Journal of structural biology · 2025Article
- Membrane Composition Modulates Vp54 Binding: A Combined Experimental and Computational Study.Pathogens (Basel, Switzerland) · 2025Article
- Molecular Dynamics Simulation Analysis of JAK1 Initial Activation: Phosphorylation-Induced Conformational Dynamics and Domain Interactions.Life (Basel, Switzerland) · 2025Article
- Elucidating the interactions between Kinesin-5/BimC and the microtubule: insights from TIRF microscopy and molecular dynamics simulations.Briefings in bioinformatics · 2025Article
- Review
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
- Integrated modeling of protein and RNA.Briefings in bioinformatics · 2024Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The family of Janus Kinases (JAKs) associated with the JAK-signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra's method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.
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