Catalytically Active MAP KAP Kinase 2 Structures in Complex with Staurosporine and ADP Reveal Differences with the Autoinhibited Enzyme
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MAP KAP kinase 2 (MK2), a Ser/Thr kinase, plays a crucial role in the inflammatory process. We have determined the crystal structures of a catalytically active C-terminal deletion form of human MK2, residues 41-364, in complex with staurosporine at 2.7 A and with ADP at 3.2 A, revealing overall structural similarity with other Ser/Thr kinases. Kinetic analysis reveals that the K(m) for ATP is very similar for MK2 41-364 and p38-activated MK2 41-400. Conversely, the catalytic rate and binding for peptide substrate are dramatically reduced in MK2 41-364. However, phosphorylation of MK2 41-364 by p38 restores the V(max) and K(m) for peptide substrate to values comparable to those seen in p38-activated MK2 41-400, suggesting a mechanism for regulation of enzyme activity.
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The C-terminus of MAPKAPKs is unstructured in all of their protein crystal structures.
“the C-terminus of MAPKAPKs is unstructured in all of their protein crystal structures (32-33).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [32]
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- Authors
- Underwood, K. W., Parris, K. D., Federico, E., Mosyak, L., Czerwinski, R. M., Shane, T., Taylor, M., Svenson, K., Liu, Y., Hsiao, C.-L., Wolfrom, S., Maguire, M., Malakian, K., Telliez, J.-B., Lin, L.-L., Kriz, R. W., Seehra, J., Somers, W. S., & Stahl, M. L.
- Affiliations
- Wyeth (US)
- Corresponding author
- Underwood, Kathryn W.
- Parris, Kevin D.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 11
- Issue
- 6
- Pages
- 627-636
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2034611095
- Cited by
- 62
- References
- 39
- Citations by year
- 2025: 1 · 2023: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 2 · 2012: 5
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (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 › Protein Tyrosine Phosphatases
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- MAPKAPK2, staurosporine, ADP, Ser/Thr kinase, p38 MAPK, kinase activation, peptide substrate binding, C-terminal deletion mutants, inflammatory signaling, kinase crystal structure
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Adenosine Diphosphate, Amino Acid Sequence, Enzyme Activation, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Molecular Structure, Sequence Alignment, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Staurosporine, Mitogen-Activated Protein Kinases, Macromolecular Substances, Intracellular Signaling Peptides and Proteins, p38 Mitogen-Activated Protein Kinases
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