title: Activation of nanoscale allosteric protein domain motion revealed by neutron spin echo spectroscopy.
abstract: NHERF1 is a multidomain scaffolding protein that assembles signaling complexes, and regulates the cell surface expression and endocytic recycling of a variety of membrane proteins. The ability of the two PDZ domains in NHERF1 to assemble protein complexes is allosterically modulated by the membrane-cytoskeleton linker protein ezrin, whose binding site is located as far as 110 Ångstroms away from the PDZ domains. Here, using neutron spin echo (NSE) spectroscopy, selective deuterium labeling, and theoretical analyses, we reveal the activation of interdomain motion in NHERF1 on nanometer length-scales and on submicrosecond timescales upon forming a complex with ezrin. We show that a much-simplified coarse-grained model suffices to describe interdomain motion of a multidomain protein or protein complex. We expect that future NSE experiments will benefit by exploiting our approach of selective deuteration to resolve the specific domain motions of interest from a plethora of global translational and rotational motions. Our results demonstrate that the dynamic propagation of allosteric signals to distal sites involves changes in long-range coupled domain motions on submicrosecond timescales, and that these coupled motions can be distinguished and characterized by NSE.
authors.affiliation: Institut Laue-Langevin, Grenoble, France.
authors.forename: Bela
authors.initials: B
authors.lastname: Farago
authors.forename: Jianquan
authors.initials: J
authors.lastname: Li
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cornilescu
authors.forename: David J E
authors.initials: DJ
authors.lastname: Callaway
authors.forename: Zimei
authors.initials: Z
authors.lastname: Bu
mesh_terms: D000495:Allosteric Site; D008958:Models, Molecular; D009038:Motion; D053758:Nanoparticles / Q000737:chemistry*; D009502:Neutrons; D010316:Particle Size; D010750:Phosphoproteins / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods*
chemical_list: D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor