Title
Molecular Conformation of the Full-Length Tumor Suppressor NF2/Merlin—A Small-Angle Neutron Scattering Study
Author
Jahan Ali Khajeh, Jeong Ho Ju, Moussoubaou Atchiba, Marc Allaire, Christopher Stanley, William T. Heller, David J.E. Callaway, Zimei Bu
Year
2014
Journal
Journal of Molecular Biology
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.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Ligand binding, Biochemistry