ArticlePloS one2015
Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- The molecular sociology of NHERF1 PDZ proteins controlling renal hormone-regulated phosphate transport.Bioscience reports · 2024Article
- Mutations in an unrecognized internal NPT2A PDZ motif disrupt phosphate transport and cause congenital hypophosphatemia.The Biochemical journal · 2023Article
- RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein.The Journal of biological chemistry · 2022Article
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- Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box.International journal of molecular sciences · 2021Review
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- Parallel Post-Translational Modification Scanning Enhancing Hydrogen-Deuterium Exchange-Mass Spectrometry Coverage of Key Structural Regions.Analytical chemistry · 2019Article
- Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport.The Journal of biological chemistry · 2019Article
- NaPi-IIa interacting partners and their (un)known functional roles.Pflugers Archiv : European journal of physiology · 2019Review
- Origins of PDZ Binding Specificity. A Computational and Experimental Study Using NHERF1 and the Parathyroid Hormone Receptor.Biochemistry · 2017Article
- Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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- Multisite NHERF1 phosphorylation controls GRK6A regulation of hormone-sensitive phosphate transport.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Na+/H+ Exchanger Regulatory Factor-1 (NHERF1) is a scaffolding protein containing 2 PDZ domains that coordinates the assembly and trafficking of transmembrane receptors and ion channels. Most target proteins harboring a C-terminus recognition motif bind more-or-less equivalently to the either PDZ domain, which contain identical core-binding motifs. However some substrates such as the type II sodium-dependent phosphate co-transporter (NPT2A), uniquely bind only one PDZ domain. We sought to define the structural determinants responsible for the specificity of interaction between NHERF1 PDZ domains and NPT2A. By performing all-atom/explicit-solvent molecular dynamics (MD) simulations in combination with biological mutagenesis, fluorescent polarization (FP) binding assays, and isothermal titration calorimetry (ITC), we found that in addition to canonical interactions of residues at 0 and -2 positions, Arg at the -1 position of NPT2A plays a critical role in association with Glu43 and His27 of PDZ1 that are absent in PDZ2. Experimentally introduced mutation in PDZ1 (Glu43Asp and His27Asn) decreased binding to NPT2A. Conversely, introduction of Asp183Glu and Asn167His mutations in PDZ2 promoted the formation of favorable interactions yielding micromolar KDs. The results describe novel determinants within both the PDZ domain and outside the canonical PDZ-recognition motif that are responsible for discrimination of NPT2A between two PDZ domains. The results challenge general paradigms for PDZ recognition and suggest new targets for drug development.
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