title: Molecular conformation of the full-length tumor suppressor NF2/Merlin--a small-angle neutron scattering study.
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.
authors.affiliation: Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA.
authors.forename: Jahan
authors.initials: J
authors.lastname: Ali Khajeh
authors.affiliation: Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA.
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Ju
authors.affiliation: Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA.
authors.forename: Moussoubaou
authors.initials: M
authors.lastname: Atchiba
authors.affiliation: Photon Sciences Directorate, Brookhaven National Laboratory, NY, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Allaire
authors.affiliation: Biology and Soft Matter Division, Oak Ridge National Laboratory, TN, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stanley
authors.affiliation: Biology and Soft Matter Division, Oak Ridge National Laboratory, TN, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Heller
authors.affiliation: Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA.
authors.forename: David J E
authors.initials: DJ
authors.lastname: Callaway
authors.affiliation: Department of Chemistry, City College of New York and CUNY Graduate Center, NY, USA. Electronic address: zbu@ccny.cuny.edu.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Bu
mesh_terms: D002151:Calorimetry; D002942:Circular Dichroism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D025581:Neurofibromin 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D033363:Neutron Diffraction / Q000379:methods*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D053838:Scattering, Small Angle; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D025581:Neurofibromin 2; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor
keywords: Ezrin; Merlin; neurofibromatosis type 2; phosphatidylinositol 4,5-bisphosphate; small-angle neutron scattering