Kinetic Mechanism and Inhibitor Characterization for c-jun-N-Terminal Kinase 3α1
Abstract
c-jun-N-Terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein (MAP) kinase family member expressed primarily in the brain that phosphorylates protein transcription factors including c-jun and activating transcription factor 2 (ATF2) upon activation by a variety of stress-based stimuli. In this study, the kinetic mechanism for JNK3alpha1 was determined via initial velocity patterns in the presence and absence of both ATP and ATF2 competitive inhibitors. Peptide inhibitors from both ATF2 (peptide 1) and JNK-interacting protein 1 (JIP-1) (peptide 3), derived from the homologous delta-domain JNK docking sequence, inhibited JNK3alpha1 activity in a competitive fashion versus ATF2 while being pure noncompetitive toward ATP. In contrast, peptides derived from the phosphoacceptor activation domain on ATF2 (peptides 4 and 5) were recognized neither as substrates nor as inhibitors of JNK3alpha1. AMP-PCP and compound 6, a small molecule analinopyrimidine, exhibited pure noncompetitive inhibition versus ATF2 and competitive inhibition versus ATP. Peptide inhibitors based on the delta-domain sites of JIP ( 3) and ATF2 ( 1) were not recognized by p38, also of the MAPK family, which may give insight into finding more selective inhibitors for the JNK family of kinases. Collectively these data showed that JNK3alpha1 proceeded by a random sequential kinetic mechanism and that the ATP and ATF2 substrate sites were non-interacting. Moreover, these results established the 11-mer JIP peptide ( 3) as a potent ( K i = 25 +/- 6 nM) competitive inhibitor versus ATF2 in JNK3alpha1.
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The Km of SAB (1-390) for JNK3α1 was 0.77 ± 0.09 μM, compared with the previously reported ATF2 Km of 0.16 ± 0.04 μM.
“Lastly, we measured the Km (0.77 ± 0.09 μM) of SAB (1–390) for JNK3α1, compared to Km for ATF2 = 0.16 ± 0.04 μM from our previous work (Ember et al., 2008).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Ember et al., 2008
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Selectivity of Docking Sites in MAPK Kinases
Bardwell, A. J., Frankson, E., & Bardwell, L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900080200 · Cited by 127 · see citing works
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
“Lastly, we measured the Km (0.77 ± 0.09 μM) of SAB (1– 390) for JNK3α1, compared to Km for ATF2 = 0.16 ± 0.04 μM from our previous work (Ember et al., 2008).”
MethodInfluentialSelf-citationCharacterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide
Ngoei, K. R. W., Catimel, B., Church, N., Lio, D. S., Dogovski, C., Perugini, M. A., Watt, P. M., Cheng, H.-C., Ng, D. C. H., & Bogoyevitch, M. A. (2011) · Biochemical Journal · doi:10.1042/bj20101244 · Cited by 31 · see citing works
- Authors
- Ember, B., Kamenecka, T., & LoGrasso, P.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- LoGrasso, Philip
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-02-13
- Volume
- 47
- Issue
- 10
- Pages
- 3076-3084
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2087626463
- Cited by
- 22
- References
- 44
- Citations by year
- 2018: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 5
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- JNK3, enzyme kinetic mechanism, random sequential mechanism, competitive inhibition, non-competitive inhibition, ATF2, JIP1, peptide inhibitors, AMP-PCP, compound 6, p38 MAPK, substrate specificity, ATP binding site
- MeSH terms
- Adenosine Triphosphate, Binding Sites, Enzyme Inhibitors, Kinetics, Peptides, Protein Binding, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 10, Activating Transcription Factor 2
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