Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase
Abstract Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62150-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849234687367577600 |
|---|---|
| author | Erin Skeens Federica Maschietto Ramu Manjula Shanelle Shillingford James Murphy Elias J. Lolis Victor S. Batista Anton M. Bennett George P. Lisi |
| author_facet | Erin Skeens Federica Maschietto Ramu Manjula Shanelle Shillingford James Murphy Elias J. Lolis Victor S. Batista Anton M. Bennett George P. Lisi |
| author_sort | Erin Skeens |
| collection | DOAJ |
| description | Abstract Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the MAPKs and MKPs still remains to be fully explored. Here, we sought to define the molecular mechanism of MKP5 regulation through an allosteric site within its catalytic domain. We demonstrate using crystallographic and NMR spectroscopy approaches that residue Y435 is required to maintain the structural integrity of the allosteric pocket. Along with molecular dynamics simulations, these data provide insight into how changes in the allosteric pocket propagate conformational flexibility in the surrounding loops to reorganize catalytically crucial residues in the active site. Furthermore, Y435 is required for the interaction with p38 MAPK and JNK, thereby promoting dephosphorylation. Collectively, these results demonstrate critical roles for the allosteric site in coordinating both MKP5 catalysis and MAPK binding. |
| format | Article |
| id | doaj-art-67993377e7b84121a264dd698e8cb25f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-67993377e7b84121a264dd698e8cb25f2025-08-20T04:03:03ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-62150-wDynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphataseErin Skeens0Federica Maschietto1Ramu Manjula2Shanelle Shillingford3James Murphy4Elias J. Lolis5Victor S. Batista6Anton M. Bennett7George P. Lisi8Department of Molecular Biology, Cell Biology and Biochemistry, Brown UniversityDepartment of Chemistry, New York UniversityDepartment of Pharmacology, Yale School of Medicine, Yale University School of MedicineDepartment of Chemistry, Yale UniversityDepartment of Pharmacology, Yale School of Medicine, Yale University School of MedicineDepartment of Pharmacology, Yale School of Medicine, Yale University School of MedicineDepartment of Chemistry, Yale UniversityDepartment of Pharmacology, Yale School of Medicine, Yale University School of MedicineDepartment of Molecular Biology, Cell Biology and Biochemistry, Brown UniversityAbstract Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the MAPKs and MKPs still remains to be fully explored. Here, we sought to define the molecular mechanism of MKP5 regulation through an allosteric site within its catalytic domain. We demonstrate using crystallographic and NMR spectroscopy approaches that residue Y435 is required to maintain the structural integrity of the allosteric pocket. Along with molecular dynamics simulations, these data provide insight into how changes in the allosteric pocket propagate conformational flexibility in the surrounding loops to reorganize catalytically crucial residues in the active site. Furthermore, Y435 is required for the interaction with p38 MAPK and JNK, thereby promoting dephosphorylation. Collectively, these results demonstrate critical roles for the allosteric site in coordinating both MKP5 catalysis and MAPK binding.https://doi.org/10.1038/s41467-025-62150-w |
| spellingShingle | Erin Skeens Federica Maschietto Ramu Manjula Shanelle Shillingford James Murphy Elias J. Lolis Victor S. Batista Anton M. Bennett George P. Lisi Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase Nature Communications |
| title | Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase |
| title_full | Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase |
| title_fullStr | Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase |
| title_full_unstemmed | Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase |
| title_short | Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase |
| title_sort | dynamic and structural insights into allosteric regulation on mkp5 a dual specificity phosphatase |
| url | https://doi.org/10.1038/s41467-025-62150-w |
| work_keys_str_mv | AT erinskeens dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT federicamaschietto dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT ramumanjula dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT shanelleshillingford dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT jamesmurphy dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT eliasjlolis dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT victorsbatista dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT antonmbennett dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase AT georgeplisi dynamicandstructuralinsightsintoallostericregulationonmkp5adualspecificityphosphatase |