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Cited by 304Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesProtein Structure and Dynamics

Crystal Structures of MAP Kinase p38 Complexed to the Docking Sites on Its Nuclear Substrate MEF2A and Activator MKK3b

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Chang, Chung-I, Xu, Bing-e, Akella, Radha, Cobb, Melanie H, Goldsmith, Elizabeth J·2002·Molecular Cell
DOI 10.1016/s1097-2765(02)00525-7
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Abstract

The structures of the MAP kinase p38 in complex with docking site peptides containing a phi(A)-X-phi(B) motif, derived from substrate MEF2A and activating enzyme MKK3b, have been solved. The peptides bind to the same site in the C-terminal domain of the kinase, which is both outside the active site and distinct from the "CD" domain previously implicated in docking site interactions. Mutational analysis on the interaction of p38 with the docking sites supports the crystallographic models and has uncovered two novel residues on the docking groove that are critical for binding. The two peptides induce similar large conformational changes local to the peptide binding groove. The peptides also induce unexpected and different conformational changes in the active site, as well as structural disorder in the phosphorylation lip.

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  • The first crystal structures of a MAPK, p38, bound to a KIM peptide (MEF2A and MKK3b) were described in 2002 by the Goldsmith laboratory.

    “The first crystal structures of a MAPK, p38, bound to a KIM peptide (MEF2A, a substrate, and MKK3b, an activating kinase) were described in 2002 by the Goldsmith laboratory.42”

    From Molecular basis of MAP kinase regulation (2013) · cites this paper as [42]

  • Allostery among the catalytic site, activation loop, and peptide-docking site is well documented for ERK and p38 MAPKs but is less understood for JNK.

    “Allostery among the catalytic site, A-loop, and peptide-docking site of ERK and p38 MAPKs has been well documented (Chang et al., 2002; Goldsmith, 2011; Lee et al., 2004; Wang et al., 1997; Zhang et al., 1994; Zhou et al., 2006a, 2006b), but much less is known about these processes for JNK.”

    From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Chang et al., 2002

  • MAPK docking is a well-characterized protein-peptide interaction system.

    “At the structural level, MAPK docking is a well characterized protein-peptide interaction system (9, 12-16).”

    From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [9]

  • MAPKs phosphorylate serine and threonine followed by proline and bind D-motifs of about 8-12 amino acids that satisfy a loose consensus.

    “For example, MAPKs phosphorylate serine and threonine residues that are followed by proline (called a S/TP target site or motif) and they also bind to docking (D)-motifs, which are ~8-12 amino acid long fragments satisfying a loose consensus sequence (9)”

    From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [9]

  • The N-terminal region of the MKK6 D-motif was not visible in the electron density map of the pepMKK6-p38α complex, similar to the p38α-pepMEF2A and p38α-pepMKK3 complexes.

    “Similarly to the previously determined structures of the p38α-pepMEF2A and p38α-pepMKK3 complexes, the N-terminal region of the MKK6 D-motif cannot be seen on the electron density map of the pepMKK6-p38α complex (9).”

    From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [9]

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Authors
Chang, C.-I., Xu, B.-E., Akella, R., Cobb, M. H., & Goldsmith, E. J.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Goldsmith, Elizabeth J
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2002-06
Volume
9
Issue
6
Pages
1241-1249
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/s1097-2765(02)00525-7
OpenAlex
W2017012572
Cited by
302
References
42
Citations by year
2026: 3 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 2 · 2021: 8 · 2020: 12 · 2019: 9 · 2018: 6 · 2017: 10 · 2016: 13 · 2015: 7 · 2014: 7 · 2013: 15 · 2012: 11
FWCI
8.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK 46993, R01DK046993)
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
MEF2A, docking site, kinase-substrate interactions, C-terminal domain, peptide binding groove, conformational change, MAPK activation
MeSH terms
Adenosine Triphosphate, Amino Acid Sequence, Binding Sites, Cell Line, DNA-Binding Proteins, Humans, Models, Molecular, Molecular Sequence Data, Peptides, Protein-Tyrosine Kinases, Transcription Factors, Molecular Structure, Mutagenesis, Site-Directed, Myogenic Regulatory Factors, Crystallography, X-Ray, Protein Structure, Quaternary, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MADS Domain Proteins, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 3, MEF2 Transcription Factors

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