p38α MAP Kinase Dimers with Swapped Activation Segments and a Novel Catalytic Loop Conformation

Rothweiler, U.; Åberg, Espen; Johnson, Kenneth A.; Hansen, Tom Egil; Jørgensen, Jorunn B.; Engh, Richard A.

doi:10.1016/j.jmb.2011.06.013

Cited by 15 publications

(18 citation statements)

References 41 publications

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“…In addition to the well-characterized activation of p38α via phosphorylation at both residues of the p38α TxY activation loop motif by dual T/Y-specific MAPK kinases, p38α is activated via a noncanonical pathway via homodimerization. 21 These data suggested that c-Abl mediates p38α activation via both canonical (Y182) and noncanonical (Y323) pathways.…”

Section: Resultsmentioning

confidence: 93%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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Section: Resultsmentioning

confidence: 93%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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“…8 ). Of note, the mechanisms of mutant-controlled energy landscape shift that can either promote or impede the swapped dimer, are not limited to Bax, but observed for other proteins, including Grb7 62 , E-cadherin 63 , p38α 64 , LRRK2 65 , Protein L 66 , SPAK 67 and cytochrome complexes 68 . This suggests that the triggering or blocking swapped protein assemblies by mutations is a general phenomenon that plays an important role in human metabolism and broadly in the cell 69 , including in membrane pores as is the case here.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

Zhang

Zheng

Nussinov

et al. 2016

Sci Rep

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Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer → dimer → membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer → dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail.

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“…[5] It has also been crystallized as ab ound ligand to Abl, BMX, BTK, EphA4,L yn, p38a,p 38MAP,a nd Src kinases. [7][8][9][10][11][12][13][14] The common manner by which it binds to each of thesek inases suggestsi t should be similar for many other kinases as well. This may,i n part, explain the sidee ffects of the compound at clinical dosage.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors

et al. 2016

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Derivatives of dasatinib were synthesized via esterification with 25 carboxylic acids including amino acids and fatty acids by extending the inhibitor to interact with more diverse sites and to improve specificity. Dasatinib-L-arginine derivative (Das-R, 7) was the most potent of the inhibitors tested with IC50 values of 4.4 nM, <0.25 nM, and <0.45 nM against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src belonged to compound 18 (Das-C10) with an IC50 of 3.2 μM for Csk compared to 35 nM for Src. Furthermore, many compounds displayed increased selectivity toward Src, as compared with Abl. Compounds 15 (Das-E) and 13 (Das-C) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 = 2.06 μM) was significantly more potent than Das (IC50 = 26.3 μM) against Panc-1 cells while they both showed an IC50 < 51.2 pM against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed a good agreement with the experimental results and rationalized differences in selectivity of the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of dasatinib scaffold, providing useful insights into mechanisms of kinase selectivity.

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p38α MAP Kinase Dimers with Swapped Activation Segments and a Novel Catalytic Loop Conformation

Cited by 15 publications

References 41 publications

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors

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