Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5
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MAP kinase phosphatases (MKPs) have crucial roles in regulating the signaling activity of MAP kinases and are potential targets for drug discovery against human diseases. These enzymes contain a catalytic domain (CD) as well as a binding domain (BD) that help recognize the target MAP kinase. We report here the crystal structures at up to 2.2 Å resolution of the BD and CD of human MKP5 and compare them to the known structures from other MKPs. Dramatic structural differences are observed between the BD of MKP5 and that of MKP3 determined previously by NMR. In particular, the cluster of positively charged residues that is important for MAP kinase binding is located in completely different positions in the two structures, with a distance of 25 Å between them. Moreover, this cluster is α‐helical in MKP5, while it forms a loop followed by a β‐strand in MKP3. These large structural differences could be associated with the distinct substrate preferences of these phosphatases, but further studies are needed to confirm this. The CD of MKP5 is observed in an active conformation, and two loops in the active site have backbone shifts of up to 5 Å relative to the inactive CDs from other MKPs.
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In DUSPs/MKPs, the KIM is not a linear peptide but part of the structured MKBD domain and is much more constrained than that of MKKs or KIM-PTPs.
“In DUSPs/MKPs, the KIM is not a linear peptide but instead part of the structured MKBD domain [35][36][37] and thus is much more constrained than that of e.g.MKKs or KIM-PTPs.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [37]
The MKBDs of DUSP6/MKP3, DUSP10/MKP5, and DUSP16/MKP7 all adopt a common mixed α/β-fold that is highly similar to that of sulfurtransferases (rhodaneses) and the DUSP Cdc25A.
“All adopt a common mixed a/b-fold that is highly similar to that of sulfurtransferases (rhodaneses) and the DUSP Cdc25A.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [37]
The MKBDs of DUSP6/MKP3, DUSP10/MKP5, and DUSP16/MKP7 have been structurally characterized.
“The MKBDs of DUSP6/MKP3 36 (NMR spectroscopy), DUSP10/MKP5 37 (X-ray crystallography) and DUSP16/MKP7 35 (X-ray crystallography) have been structurally characterized.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [37]
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References 45 · Cited by 31
- Authors
- Tao, X., & Tong, L.
- Affiliations
- Columbia University (US)
- Corresponding author
- Tong, Liang
- ORCID
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2007-05
- Volume
- 16
- Issue
- 5
- Pages
- 880-886
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2206639
- OpenAlex
- W1990509986
- Cited by
- 31
- References
- 45
- Citations by year
- 2025: 3 · 2024: 4 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- MAP kinase phosphatase, MKP-3, catalytic domain, crystal structure, substrate specificity, active site conformation
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Molecular Sequence Data, Protein Binding, Sequence Alignment, Protein Tyrosine Phosphatases, Crystallography, X-Ray, Catalytic Domain, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases
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