Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Int J Mol Sci. 2021 Jan 22;22(3):1087. doi: 10.3390/ijms22031087.
Na/H exchange factor-1 (NHERF1), a multidomain PDZ scaffolding phosphoprotein, is required for the type II sodium-dependent phosphate cotransporter (NPT2A)-mediated renal phosphate absorption. Both PDZ1 and PDZ2 domains are involved in NPT2A-dependent phosphate uptake. Though harboring identical core-binding motifs, PDZ1 and PDZ2 play entirely different roles in hormone-regulated phosphate transport. PDZ1 is required for the interaction with the C-terminal PDZ-binding sequence of NPT2A (-TRL). Remarkably, phosphocycling at Ser distant from PDZ1, the penultimate step for both parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) regulation, controls the association between NHERF1 and NPT2A. PDZ2 interacts with the C-terminal PDZ-recognition motif (-TRL) of G Protein-coupled Receptor Kinase 6A (GRK6A), and that promotes phosphorylation of Ser. The compelling biological puzzle is how PDZ1 and PDZ2 with identical GYGF core-binding motifs specifically recognize distinct binding partners. Binding determinants distinct from the canonical PDZ-ligand interactions and located "outside the box" explain PDZ domain specificity. Phosphorylation of NHERF1 by diverse kinases and associated conformational changes in NHERF1 add more complexity to PDZ-binding diversity.
钠/氢交换因子 1（NHERF1）是一种具有多个 PDZ 结构域的支架磷酸化蛋白，是 II 型钠依赖性磷酸盐共转运蛋白（NPT2A）介导的肾脏磷酸盐吸收所必需的。PDZ1 和 PDZ2 结构域都参与 NPT2A 依赖的磷酸盐摄取。虽然 PDZ1 和 PDZ2 都含有相同的核心结合基序，但它们在激素调节的磷酸盐转运中发挥着完全不同的作用。PDZ1 对于与 NPT2A 的 C 末端 PDZ 结合序列（-TRL）的相互作用是必需的。值得注意的是，在 PDZ1 远处的丝氨酸处发生磷酸循环，这是甲状旁腺激素（PTH）和成纤维细胞生长因子 23（FGF23）调节的倒数第二步，控制着 NHERF1 与 NPT2A 之间的关联。PDZ2 与 G 蛋白偶联受体激酶 6A（GRK6A）的 C 末端 PDZ 识别基序（-TRL）相互作用，从而促进丝氨酸的磷酸化。引人注目的生物学难题是，具有相同 GYGF 核心结合基序的 PDZ1 和 PDZ2 如何特异性识别不同的结合伙伴。与典型 PDZ 配体相互作用不同的结合决定因素位于“盒外”，解释了 PDZ 结构域的特异性。不同激酶对 NHERF1 的磷酸化以及 NHERF1 相关的构象变化增加了 PDZ 结合多样性的复杂性。
