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Molecular basis of MAPK-activated protein kinase 2:p38 assembly
Open accessAbstract
p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38α isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-Å resolution crystal structure of the unphosphorylated complex between p38α and MK2. These protein kinases bind “head-to-head,” present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366–Ala-390, which includes the bipartite nuclear localization signal, binds to the p38α-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38α binary assembly. The MK2 residues 345–365, containing the nuclear export signal, block access to the p38α active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38α and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein–protein interactions involving signal transduction proteins.
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“In addition, while the structure of p38 bound to its substrate, the MAPKAP-2 (MK2) kinase was the first structure to show that p38 is capable of binding KIM peptides bi-directionally 54,55 (that is, in a C-to-N, versus the more common N-to-C direction; Figs.2(A,B))”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [55]
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Metadata
- Authors
- White, A., Pargellis, C. A., Studts, J. M., Werneburg, B. G., & Farmer, B. T.
- Affiliations
- Departments of *Medicinal Chemistry,
- Immunology and Inflammation, and
- Boehringer Ingelheim (United States) (US)
- Brandeis University (US)
- ORCID
- Studts, Joey M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-04-10
- Volume
- 104
- Issue
- 15
- Pages
- 6353-6358
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1851067
- OpenAlex
- W2056171538
- Cited by
- 111
- References
- 51
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 10 · 2013: 7 · 2012: 11
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
- Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
- Basic Energy Sciences (DE-AC02, DE-AC- 02-06CH11357, AC02‐06CH11357, 06CH11357)
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- p38 MAPK, MAPKAPK2, protein-protein interaction, crystal structure, nuclear localization signal, nuclear export signal, signal transduction, proinflammatory cytokine production
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Animals, Cloning, Molecular, Humans, Models, Molecular, Phosphorylation, Protein Binding, Protein Conformation, X-Ray Diffraction, Signal Transduction, Protein Serine-Threonine Kinases, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, p38 Mitogen-Activated Protein Kinases, Mice
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