Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box.

摘要: Na+/H+ exchange factor-1 (NHERF1), a multidomain PDZ scaffolding phosphoprotein, is required for the type II sodium-dependent phosphate cotransporter (NPT2A)-mediated renal absorption. Both PDZ1 and PDZ2 domains are involved in NPT2A-dependent uptake. Though harboring identical core-binding motifs, play entirely different roles hormone-regulated transport. interaction with C-terminal PDZ-binding sequence of NPT2A (-TRL). Remarkably, phosphocycling at Ser290 distant from PDZ1, penultimate step both parathyroid hormone (PTH) fibroblast growth factor-23 (FGF23) regulation, controls association between NHERF1 NPT2A. interacts PDZ-recognition motif (-TRL) G Protein-coupled Receptor Kinase 6A (GRK6A), that promotes phosphorylation Ser290. The compelling biological puzzle how GYGF motifs specifically recognize distinct binding partners. Binding determinants canonical PDZ-ligand interactions located "outside box" explain domain specificity. Phosphorylation by diverse kinases associated conformational changes add more complexity to diversity.