Structural basis of p38α regulation by hematopoietic tyrosine phosphatase
Open accessAbstract
NMR and ITC are used to define essential features of a p38α phosphatase interface that extend beyond the classic KIM binding site, and SAXS analysis software, incorporating NMR chemical shift data, are developed and applied to build a model of the p38α-HePTP complex. MAP kinases regulate essential cellular events, including cell growth, differentiation and inflammation. The solution structure of a complete MAPK–MAPK-regulatory protein complex, p38α–HePTP, was determined, enabling a comprehensive investigation of the molecular basis of specificity and fidelity in MAPK regulation. Structure determination was achieved by combining NMR spectroscopy and small-angle X-ray scattering data with a new ensemble calculation–refinement procedure. We identified 25 residues outside of the HePTP kinase interaction motif necessary for p38α recognition. The complex adopts an extended conformation in solution and rarely samples the conformation necessary for kinase deactivation. Complex formation also does not affect the N-terminal lobe, the activation loop of p38α or the catalytic domain of HePTP. Together, these results show how the downstream tyrosine phosphatase HePTP regulates p38α and provide for fundamentally new insights into MAPK regulation and specificity.
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Differences in the NMR spectra of MAPKs (p38a > ERK2 > JNK1) provide the first indications that dynamics likely plays a key role in their biological function.
“The latter point seems to be especially critical for MAPKs and the differences in their NMR spectra (spectra quality of MAPKs tested by the authors is p38a>ERK2JNK1) 58,61,65 are providing the first indications that dynamics likely plays a key role in their biological function.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
The discrimination factor of DUSP16/MKP7 for p38 versus ERK is only 0.7.
“Indeed, we have observed the same behavior of KIM peptides/proteins using ITC; i.e., the discrimination factor of DUSP16/MKP7 (a p38/ JNK specific DUSP) for p38 versus ERK is only 0.7.57,58”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
The quality of 2D [1H,15N] TROSY spectra of MAPKs is significantly different from one another, with often many fewer peaks detected than expected, despite their nearly identical 3D structures.
“Interestingly, the quality of the 2D [ 1 H, 15 N] TROSY spectra of MAPKs are significantly different from one another, with often many fewer peaks detected than expected, despite their nearly identical 3D structures.58,61,65”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
The ensemble model showed that the catalytic domain of HePTP is localized below the p38 KIM-binding groove and fluctuates in a fan-like motion below p38, explaining why crystallization of this complex has proven intractable.
“The ensemble model showed that the catalytic domain of HePTP is localized below the p38 KIM-binding groove and fluctuates in a fan-like motion below p38; explaining why the crystallization of this complex has proven intractable [Fig.4(B)].”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
EROS-NMR allowed the relative orientation of p38 and HePTP that best fits both the NMR CSP constraints and the experimental SAXS data to be determined.
“This allowed the relative orientation of p38 and HePTP that best fits both the NMR CSP constrains and the experimental SAXS data to be determined [Fig.4(A)].58”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
Sequence-specific backbone assignment has been achieved for p38a (82%), activated pTpYp38a (56%), and ERK2 (65%), including key MAPK regulatory elements.
“The basis of any NMR spectroscopy analysis is the sequence-specific backbone assignment, which has been achieved for p38a 47,58,61 (82%), activated pTpYp38a 69 (56%) and ERK2 65 (65%) and include key MAPK regulatory elements, especially the KIM binding pockets (93%/95% for p38a/ERK2) the glycine-rich loops (100%/100% for p38a/ERK2) and the activation loops (83%/none for p38a/ERK2).”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
Residue L108 from p38, which functions as a hinge connecting the p38 N- and C-terminal lobes, experiences CSPs with HePTP and PTPSL, but not STEP.
“Second, residue L108 from p38, which functions as a hinge connecting the p38 Nand C-terminal lobes, experiences CSPs with HePTP and PTPSL, but not STEP.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
HePTP, but not PTPSL or STEP, also interacts with p38 via its kinase specificity sequence (KIS; the HePTP KIM-KIS is composed of residues 15-56), resulting in the CSP of residues outside the p38 KIM binding groove.
“Third, HePTP, but not PTPSL or STEP, also interacts with p38 via its kinase specificity sequence (KIS; the HePTP KIMKIS is composed of residues 15-56), resulting in the CSP of residues outside the p38 KIM binding groove.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
The p38:HePTP complex is elongated in solution.
“This observation, coupled with SAXS experiments that showed that the p38:HePTP complex is elongated in solution and reverse titrations that allowed us to unequivocally define which HePTP residues bind p38, led to the development of new computational procedure, ensemble refinement of SAXS (EROS)-NMR.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
There are key differences in the mechanism of binding of HePTP, STEP, and PTPSL with p38.
“These experiments showed that while there are similarities, there are also key differences in the mechanism of binding of HePTP, STEP, and PTPSL with p38.58,60”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
While the mode of KIM binding to p38 is largely conserved among the KIM-PTP family, with the KIMs from PTPSL/STEP and HePTP engaging residues within all four hydrophobic and both electrostatic pockets of the MAPK KIM binding groove, they perturb it differently, especially in the U_A and U_B hydrophobic pockets.
“First, while the mode of KIM binding to p38 is largely conserved among the KIM-PTP family, with the KIMs from PTPSL/STEP and HePTP engaged residues within all four hydrophobic both electrostatic pockets of the MAPK KIM binding groove, they perturb it differently, especially in the U A and U B hydrophobic pockets.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
While the p38:HePTP and p38:PTPSL complexes are elongated in solution, the p38:STEP complex is compact.
“Fourth, while the p38:HePTP and p38:PTPSL complexes are elongated in solution, the p38:STEP complex is compact.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
NMR studies of p38 with the KIM-containing family of PTPs have demonstrated that while the KIM peptides of these proteins bind p38 via quite similar mechanisms, they interact with p38 outside of the KIM binding groove very differently, explaining their different biological activities.
“Specifically, NMR studies of p38 with the KIM containing family of PTPs have unequivocally demonstrated that while the KIM peptides of these proteins bind p38 via quite similar mechanisms, they interact with p38 outside of the KIM binding groove very differently explaining their different biological activities.”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [58]
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BindingDB Entry 50000133: Design, Synthesis, and Biological Evaluation of Novel Type I
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- Authors
- Francis, D. M., Różycki, B., Koveal, D., Hummer, G., Page, R., & Peti, W.
- Affiliations
- Brown University (US)
- National Institutes of Health (US)
- Corresponding author
- Page, Rebecca
- Peti, Wolfgang
- Venue
- Nature Chemical Biology
- Published
- 2011-11-06
- Volume
- 7
- Issue
- 12
- Pages
- 916-924
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3657131
- OpenAlex
- W2080285527
- Cited by
- 79
- References
- 47
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 10 · 2013: 8 · 2012: 3
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM008275, R01GM100910, T32GM007601)
- National Center for Research Resources (S10RR017269)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- p38α MAPK, protein tyrosine phosphatase, protein-protein interaction, solution structure, complex conformation, activation loop, enzyme specificity
- MeSH terms
- Amino Acid Sequence, Models, Molecular, Molecular Sequence Data, Protein Conformation, Structure-Activity Relationship, Substrate Specificity, Nuclear Magnetic Resonance, Biomolecular, Mitogen-Activated Protein Kinase 14, Protein Tyrosine Phosphatase, Non-Receptor Type 6
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