Structural Basis of Substrate Recognition by Hematopoietic Tyrosine Phosphatase,
Open accessAbstract
Hematopoietic tyrosine phosphatase (HePTP) is one of three members of the kinase interaction motif (KIM) phosphatase family which also includes STEP and PCPTP1. The KIM-PTPs are characterized by a 15 residue sequence, the KIM, which confers specific high-affinity binding to their only known substrates, the MAP kinases Erk and p38, an interaction which is critical for their ability to regulate processes such as T cell differentiation (HePTP) and neuronal signaling (STEP). The KIM-PTPs are also characterized by a unique set of residues in their PTP substrate binding loops, where 4 of the 13 residues are differentially conserved among the KIM-PTPs as compared to more than 30 other class I PTPs. One of these residues, T106 in HePTP, is either an aspartate or asparagine in nearly every other PTP. Using multiple techniques, we investigate the role of these KIM-PTP specific residues in order to elucidate the molecular basis of substrate recognition by HePTP. First, we used NMR spectroscopy to show that Erk2-derived peptides interact specifically with HePTP at the active site. Next, to reveal the molecular details of this interaction, we solved the high-resolution three-dimensional structures of two distinct HePTP-Erk2 peptide complexes. Strikingly, we were only able to obtain crystals of these transient complexes using a KIM-PTP specific substrate-trapping mutant, in which the KIM-PTP specific residue T106 was mutated to an aspartic acid (T106D). The introduced aspartate side chain facilitates the coordination of the bound peptides, thereby stabilizing the active dephosphorylation complex. These structures establish the essential role of HePTP T106 in restricting HePTP specificity to only those substrates which are able to interact with KIM-PTPs via the KIM (e.g., Erk2, p38). Finally, we describe how this interaction of the KIM is sufficient for overcoming the otherwise weak interaction at the active site of KIM-PTPs.
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While the KIM is required for binding, residues outside the KIM contribute to both binding and specificity.
“While the KIM is required for binding, 38,39 multiple reports have shown that residues outside the KIM contribute to both binding and specificity.40,41”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [38]
The DUSP active site is shallow, more similar to the depth of the active sites of serine/threonine specific phosphatases than to that of tyrosine phosphatases.
“the DUSP active site is shallow 11,34 -more similar to the depth of the active sites of serine/ threonine specific phosphatases [79][80][81] -when directly compared with that of tyrosine phosphatases, 38”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [38]
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- Authors
- Critton, D. A., Tortajada, A., Stetson, G., Peti, W., & Page, R.
- Affiliations
- Brown University (US)
- Corresponding author
- Page, Rebecca
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-11-20
- Volume
- 47
- Issue
- 50
- Pages
- 13336-13345
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC2908255
- OpenAlex
- W2087147338
- Cited by
- 28
- References
- 47
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 2 · 2013: 7
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (Y01 GM000080)
- National Center for Research Resources (P20 RR 16457, P20RR016457, S10RR017269)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- substrate recognition, ERK2, p38 MAPK, substrate-binding loop, dephosphorylation, substrate specificity, STEP, T cell differentiation
- MeSH terms
- Amino Acid Sequence, Hematopoiesis, Humans, Molecular Sequence Data, Phosphorylation, Protein Conformation, Substrate Specificity, Mutagenesis, Site-Directed, Conserved Sequence, Crystallography, X-Ray, Catalytic Domain, Amino Acid Motifs, Protein Tyrosine Phosphatases, Non-Receptor
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