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Peer-reviewedCC BY-NC-NDCurrent research in structural biology

Molecular dynamics analysis of T567 phosphorylation-induced conformational changes in ezrin.

  • Sai Li1,2
  • Jinmei Pan1
  • Lirui Lin3
  • Liangli Hong1
  • En-Min Li2,4
  • Yang Zeng5
  • Li-Yan Xu4,6
  • Geng Dong1,2,5
6 affiliations
  1. 1Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, PR China.
  2. 2Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China.
  3. 3Department of Bioinformatics, Shantou University Medical College, Shantou, 515041, PR China.
  4. 4Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China.
  5. 5Medical Informatics Research Center, Shantou University Medical College, Shantou, 515041, PR China.
  6. 6Cancer Research Center, Shantou University Medical College, Shantou, 515041, PR China.
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Abstract

Ezrin, a key member of the ERM (Ezrin-Radixin-Moesin) family, links the plasma membrane to the actin cytoskeleton and is regulated by a conformational switch between closed and open states. Although phosphatidylinositol 4,5-bisphosphate binding and phosphorylation at Thr567 are known to promote Ezrin activation, the associated conformational mechanism remains incompletely understood. Here, we combined Martini coarse-grained molecular dynamics simulations with enhanced sampling, all-atom molecular dynamics simulations, and MM/PBSA calculations to compare wild-type Ezrin with the phosphomimetic T567D mutant. The simulations indicate that T567 phosphorylation destabilizes the FERM/C-ERMAD interface, promotes domain separation, and facilitates exposure of membrane- and actin-binding sites. Computational analysis of binding free energies further demonstrates that the interaction between FERM and C-ERMAD is attenuated due to the phosphorylation of T567. Finally, a stepwise dissociation mechanism for the C-ERMAD α-helices is proposed. These results support a model in which T567 phosphorylation primarily promotes the initial transition toward an open conformation, whereas complete unfolding and full activation likely require additional events, including PIP2 binding, recruitment of partner proteins, and interaction with actin filaments.

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Cite

BibTeXRIS
BibTeX
@article{li2026molecular,
  title = {{Molecular dynamics analysis of T567 phosphorylation-induced conformational changes in ezrin.}},
  author = {Sai Li and Jinmei Pan and Lirui Lin and Liangli Hong and En-Min Li and Yang Zeng and Li-Yan Xu and Geng Dong},
  journal = {Current research in structural biology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.crstbi.2026.100200},
  url = {https://europepmc.org/article/MED/42921013},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Molecular dynamics analysis of T567 phosphorylation-induced conformational changes in ezrin.
AU  - Sai Li
AU  - Jinmei Pan
AU  - Lirui Lin
AU  - Liangli Hong
AU  - En-Min Li
AU  - Yang Zeng
AU  - Li-Yan Xu
AU  - Geng Dong
PY  - 2026
DA  - 2026/10/17
JO  - Current research in structural biology
DO  - 10.1016/j.crstbi.2026.100200
UR  - https://europepmc.org/article/MED/42921013
AB  - Ezrin, a key member of the ERM (Ezrin-Radixin-Moesin) family, links the plasma membrane to the actin cytoskeleton and is regulated by a conformational switch between closed and open states. Although phosphatidylinositol 4,5-bisphosphate binding and phosphorylation at Thr567 are known to promote Ezrin activation, the associated conformational mechanism remains incompletely understood. Here, we combined Martini coarse-grained molecular dynamics simulations with enhanced sampling, all-atom molecular dynamics simulations, and MM/PBSA calculations to compare wild-type Ezrin with the phosphomimetic T567D mutant. The simulations indicate that T567 phosphorylation destabilizes the FERM/C-ERMAD interface, promotes domain separation, and facilitates exposure of membrane- and actin-binding sites. Computational analysis of binding free energies further demonstrates that the interaction between FERM and C-ERMAD is attenuated due to the phosphorylation of T567. Finally, a stepwise dissociation mechanism for the C-ERMAD α-helices is proposed. These results support a model in which T567 phosphorylation primarily promotes the initial transition toward an open conformation, whereas complete unfolding and full activation likely require additional events, including PIP2 binding, recruitment of partner proteins, and interaction with actin filaments.
SN  - 2665-928X
ER  -