Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
Open accessAbstract
Significance: Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses. We have determined a two-domain crystal structure containing the pseudokinase and kinase domains from the JAK family member TYK2, which identifies an inhibitory interaction interface between the two domains. Cancer-associated mutations found in other JAK family members map to this inhibitory interaction site, whereas analogous mutations in TYK2 cause in vitro activation of the kinase. This study identifies a mechanism for pseudokinase-mediated autoinhibition of the TYK2 kinase domain and suggests a means by which cancer-associated JAK mutations induce aberrant kinase activity.
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JAKs have four structural domains: N-terminal FERM, SH2, catalytically active JH1 kinase, and pseudo-kinase JH2; JH2 is enzymatically inactive but represses kinase activity.
“Recent X-ray crystal structural studies have provided a clearer delineation of JAK structural architecture, with four distinct domains: 1) N-terminal band 4.1, ezrin, radixin, moesin (FERM) domain; 2) SH2 domain; 3) the catalytically active JH1 kinase domain located at the C-terminal end; and 4) the pseudo-kinase domain (JH2), located adjacent to it, which is enzymatically inactive but has a cruc”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lupardus et al., 2014
The introductory passage describes four JAK domains in the stated order, and the Results show that the TYK2 pseudokinase inhibits kinase activity. But the introduction also reports weak catalytic activity in the JAK2 pseudokinase, so the categorical claim that JH2 is enzymatically inactive is not supported. Our copy provides no page number for these passages. (LLM, conf=0.90)
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Cites
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Janus kinase deregulation in leukemia and lymphoma
Chen, E., Staudt, L. M., & Green, A. R. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.017 · Cited by 123 · see citing works
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Research works printed but not linked: 17
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
Dehkhoda, F., Lee, C. M. M., Medina, J., & Brooks, A. J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00035 · Cited by 304 · see citing works
Resolving <i>TYK2</i> locus genotype-to-phenotype differences in autoimmunity
Dendrou, C. A., Cortes, A., Shipman, L., Evans, H. G., Attfield, K. E., Jostins, L., Barber, T., Kaur, G., Kuttikkatte, S. B., Leach, O. A., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1974 · Cited by 264 · see citing works
Self-citation
- Authors
- Lupardus, P. J., Ultsch, M., Wallweber, H., Bir Kohli, P., Johnson, A. R., & Eigenbrot, C.
- Affiliations
- Departments of aStructural Biology and
- Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080
- Genentech (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-19
- Volume
- 111
- Issue
- 22
- Pages
- 8025-8030
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4050602
- OpenAlex
- W2141682274
- Cited by
- 229
- References
- 2
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 21 · 2023: 30 · 2022: 22 · 2021: 15 · 2020: 15 · 2019: 20 · 2018: 16 · 2017: 13 · 2016: 16 · 2015: 18 · 2014: 5
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- 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
- TYK2, Janus kinase, pseudokinase domain, protein kinase structure, JAK2 V617F mutation, receptor dimerization, kinase activation mechanism, cytokine signaling
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Humans, Insecta, Mutation, Neoplasms, Structure-Activity Relationship, Signal Transduction, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Janus Kinase 1, Janus Kinase 2, Janus Kinase 3, TYK2 Kinase
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