A Conformational Switch in the Scaffolding Protein NHERF1 Controls Autoinhibition and Complex Formation

• DOI: 10.1074/jbc.m109.074005
• Publication Date: 2009-12-31T03:01:23Z
• Authors: Shibani Bhattacharya; Zhongping Dai; Jianquan Li; Sabine Baxter; David J.E. Callaway; David Cowburn; Zimei Bu
• Keywords: PDZ domain; Linker

The mammalian Na(+)/H(+) exchange regulatory factor 1 (NHERF1) is a multidomain scaffolding protein essential for regulating the intracellular trafficking and macromolecular assembly of transmembrane ion channels receptors. NHERF1 consists tandem PDZ-1, PDZ-2 domains that interact with cytoplasmic membrane proteins C-terminal (CT) domain binds membrane-cytoskeleton linker ezrin. held in an autoinhibited state through intramolecular interactions between PDZ2 CT also includes PDZ-binding motif (-SNL). We have determined structures isolated PDZ2CT by high resolution NMR using small angle x-ray scattering as constraints. structure shows weak largely disordered PDZ ligand binding site. reveals novel helix-turn-helix subdomain allosterically coupled to putative network hydrophobic interactions. This helical increases both stability affinity extended structure. Using neutron joint refinement, we demonstrate release domain-domain upon Based on structural information, show human disease-causing mutations PDZ2, R153Q E225K, significantly reduced stability. Loss expressed cells could result failure assemble complexes are important normal physiological functions.