Phosphorylation of Tyrosine 841 Plays a Significant Role in JAK3 Activation

Sun, Shengjie; Rodriguez, Georgialina; Xie, Yixin; Guo, Wenhan; Hernandez, Alan E. Lopez; Sanchez, Jason E.; Kirken, Robert A.; Li, Lin

doi:10.3390/life13040981

Cited by 3 publications

(2 citation statements)

References 35 publications

(45 reference statements)

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“…Previously reported molecular dynamic simulations of pY841 within the JAK3 kinase domain further support its role in activation. Recently, Sun et al showed that pY841 increases the elasticity of the enzymatic cleft between N-and C-lobes, promotes the binding of ATP, and may initiate the separation of JH1-JH2 from the inactivated to activated position [35], enabling two JH1 dimers to form, as described here (Figure 7). Given the number of autophosphorylated sites identified in this study, it is likely that the Y841 region is not the sole area controlling structural stability and dimer formation.…”

Section: Discussionsupporting

confidence: 57%

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation

Rodriguez,

Martinez,

Negrete

et al. 2023

IJMS

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Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

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Section: Discussionsupporting

confidence: 57%

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation

Rodriguez,

Martinez,

Negrete

et al. 2023

IJMS

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“…The full-length activated (open) and inhibited (closed) human JAK1 structures were generated using SWISS-MODEL [ 27 ] based on activated the JAK1 dimer (PDB: 7T6F; resolution 3.60 Å) [ 19 ] and inhibited JH1-JH2 dimer (PDB: 4OLI; resolution 2.80 Å) [ 15 , 28 ]. The RMSD between the activated JAK1 model and the template (PDB: 7T6F) is 0.10 Å while the RMSD between inhibited JAK1 model and the template (PDB: 4OLI) is 0.40 Å.…”

Section: Methodsmentioning

confidence: 99%

A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape

Sun,

Rodriguez,

Zhao

et al. 2024

Briefings in Bioinformatics

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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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A Comparative Analysis of SARS-CoV-2 Variants of Concern (VOC) Spike Proteins Interacting with hACE2 Enzyme

Chen,

Quan

et al. 2024

IJMS

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In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) simulation is utilized to compare the behaviors of SARS-CoV-2 and its Variants of Concern (VOC)-Alpha, Beta, Gamma, Delta, and Omicron-with the hACE2 protein. Protein structures from the Protein Data Bank (PDB) were aligned and trimmed for consistency using Chimera, focusing on the receptor-binding domain (RBD) responsible for ACE2 interaction. MD simulations were performed using Visual Molecular Dynamics (VMD) and Nanoscale Molecular Dynamics (NAMD2), and salt bridges and hydrogen bond data were extracted from the results of these simulations. The data extracted from the last 5 ns of the 10 ns simulations were visualized, providing insights into the comparative stability of each variant’s interaction with ACE2. Moreover, electrostatics and hydrophobic protein surfaces were calculated, visualized, and analyzed. Our comprehensive computational results are helpful for drug discovery and future vaccine designs as they provide information regarding the vital amino acids in protein-protein interactions (PPIs). Our analysis reveals that the Original and Omicron variants are the two most structurally similar proteins. The Gamma variant forms the strongest interaction with hACE2 through hydrogen bonds, while Alpha and Delta form the most stable salt bridges; the Omicron is dominated by positive potential in the binding site, which makes it easy to attract the hACE2 receptor; meanwhile, the Original, Beta, Delta, and Omicron variants show varying levels of interaction stability through both hydrogen bonds and salt bridges, indicating that targeted therapeutic agents can disrupt these critical interactions to prevent SARS-CoV-2 infection.

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Phosphorylation of Tyrosine 841 Plays a Significant Role in JAK3 Activation

Cited by 3 publications

References 35 publications

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation

A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape

A Comparative Analysis of SARS-CoV-2 Variants of Concern (VOC) Spike Proteins Interacting with hACE2 Enzyme

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