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Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer
Open accessAbstract
The p38 signaling pathway is activated in response to cell stress and induces production of proinflammatory cytokines. P38alpha is phosphorylated and activated in response to cell stress by MKK3 and MKK6 and in turn phosphorylates a number of substrates, including MAPKAP kinase 2 (MK2). We have determined the crystal structure of the unphosphorylated p38alpha-MK2 heterodimer. The C-terminal regulatory domain of MK2 binds in the docking groove of p38alpha, and the ATP-binding sites of both kinases are at the heterodimer interface. The conformation suggests an extra mechanism in addition to the regulation of the p38alpha and MK2 phosphorylation states that prevents phosphorylation of substrates in the absence of cell stress. Addition of constitutively active MKK6-DD results in rapid phosphorylation of the p38alpha-MK2 heterodimer.
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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 [54]
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“These peptides bound in a reversed N- to C-terminal orientation compared to D-motif peptides (Fig. 3B-D), similar to the binding of pepMK2 to p38α (31).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [31]
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Cites
A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
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p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases
Kumar, S., Boehm, J. C., & Lee, J. C. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1177 · Cited by 1,199
A conserved docking motif in MAP kinases common to substrates, activators and regulators
Tanoue, T., Adachi, M., Moriguchi, T., & Nishida, E. (2000) · Nature Cell Biology · doi:10.1038/35000065 · Cited by 816
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Refinement of severely incomplete structures with maximum likelihood inBUSTER–TNT
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An approach to multi-copy search in molecular replacement
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FGF and stress regulate CREB and ATF‐1 via a pathway involving p38 MAP kinase and MAPKAP kinase‐2.
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Metadata
- Authors
- Haar, E. T., Prabakhar, P., Liu, X., & Lepre, C.
- Affiliations
- Vertex Pharmaceuticals (United States) (US)
- Corresponding author
- Haar, Ernst ter
- ORCID
- Liu, Xun
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 282
- Issue
- 13
- Pages
- 9733-9739
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2117941384
- Cited by
- 100
- References
- 40
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 6 · 2012: 8
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- p38α MAPK, MAPKAPK2, heterodimer, crystal structure, MKK3, MKK6, phosphorylation regulation, ATP binding site, inflammatory cytokines
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Adenosine Triphosphate, Binding Sites, Humans, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 14
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