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Updated: Jul 29, 2026
Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy
Published on: September 17, 2017
Molecular conformation of the full-length tumor suppressor NF2/Merlin--a small-angle neutron scattering study
Jahan Ali Khajeh1, Jeong Ho Ju1, Moussoubaou Atchiba1
1Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA.
Abstract:
The tumor suppressor protein Merlin inhibits cell proliferation upon establishing cell-cell contacts. Because Merlin has high level of sequence similarity to the Ezrin-Radixin-Moesin family of proteins, the structural model of Ezrin-Radixin-Moesin protein autoinhibition and cycling between closed/resting and open/active conformational states is often employed to explain Merlin function. However, recent biochemical studies suggest alternative molecular models of Merlin function. Here, we have determined the low-resolution molecular structure and binding activity of Merlin and a Merlin(S518D) mutant that mimics the inactivating phosphorylation at S518 using small-angle neutron scattering and binding experiments. Small-angle neutron scattering shows that, in solution, both Merlin and Merlin(S518D) adopt a closed conformation, but binding experiments indicate that a significant fraction of either Merlin or Merlin(S518D) is capable of binding to the target protein NHERF1. Upon binding to the phosphatidylinositol 4,5-bisphosphate lipid, the wild-type Merlin adopts a more open conformation than in solution, but Merlin(S518D) remains in a closed conformation. This study supports a rheostat model of Merlin in NHERF1 binding and contributes to resolving a controversy about the molecular conformation and binding activity of Merlin.
Insights
The tumor suppressor Merlin protein
Area of Science:
- Cell biology
- Molecular biology
- Biochemistry
Background:
- Merlin, a tumor suppressor, regulates cell proliferation via cell-cell contacts.
- Its function is often explained by structural models of the Ezrin-Radixin-Moesin (ERM) protein family.
- Recent studies suggest alternative models for Merlin's molecular function.
Purpose of the Study:
- To determine the low-resolution molecular structure and binding activity of Merlin and a phosphorylation mimic mutant (Merlin S518D).
- To investigate Merlin's conformational changes upon binding to NHERF1 and phosphatidylinositol 4,5-bisphosphate.
- To resolve controversies regarding Merlin's molecular conformation and binding activity.
Main Methods:
- Small-angle neutron scattering (SANS) to determine low-resolution molecular structures.
- Biochemical binding experiments to assess protein-protein and protein-lipid interactions.
- Analysis of wild-type Merlin and a Merlin(S518D) mutant.
Main Results:
- Both Merlin and Merlin(S518D) adopt a closed conformation in solution.
- A significant fraction of both Merlin and Merlin(S518D) can bind to the target protein NHERF1.
- Wild-type Merlin adopts a more open conformation upon binding phosphatidylinositol 4,5-bisphosphate, while Merlin(S518D) remains closed.
Conclusions:
- Findings support a rheostat model for Merlin's interaction with NHERF1.
- Merlin's conformational state is influenced by phosphorylation and binding partners.
- This study clarifies the molecular mechanisms underlying Merlin's tumor suppressor function.
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