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

Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Academic Editor: Victor Sorriba
Int. J. Mol. Sci. 2021, 22(3), 1087; https://doi.org/10.3390/ijms22031087
Received: 30 December 2020 / Revised: 15 January 2021 / Accepted: 19 January 2021 / Published: 22 January 2021
(This article belongs to the Special Issue Mechanisms of Phosphate Transport)
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 Ser290 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 Ser290. 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. View Full-Text
Keywords: PDZ domain; type II sodium-dependent phosphate cotransporter (NPT2A); parathyroid hormone (PTH); phosphate transport; PDZ-ligand interaction; binding affinity; phosphorylation PDZ domain; type II sodium-dependent phosphate cotransporter (NPT2A); parathyroid hormone (PTH); phosphate transport; PDZ-ligand interaction; binding affinity; phosphorylation
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MDPI and ACS Style

Mamonova, T.; Friedman, P.A. Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box. Int. J. Mol. Sci. 2021, 22, 1087. https://doi.org/10.3390/ijms22031087

AMA Style

Mamonova T, Friedman PA. Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box. International Journal of Molecular Sciences. 2021; 22(3):1087. https://doi.org/10.3390/ijms22031087

Chicago/Turabian Style

Mamonova, Tatyana, and Peter A. Friedman 2021. "Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box" International Journal of Molecular Sciences 22, no. 3: 1087. https://doi.org/10.3390/ijms22031087

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