Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport

Zhang, Qiangmin; Xiao, Kunhong; Paredes, José M.; Mamonova, Tatyana; Sneddon, W. Bruce; Liu, Hongda; Wang, Dawei; Li, Sheng; McGarvey, Jennifer C.; Uehling, David; Al‐awar, Rima; Joseph, Babu; Jean-Alphonse, Frédéric; Orte, Angel; Friedman, Peter A.

doi:10.1074/jbc.ra119.007421

Cited by 26 publications

(79 citation statements)

References 105 publications

(143 reference statements)

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“…Knocking down Grk6a by siRNA blocks Npt2a-dependent phosphate uptake in response to PTH [ 63 ]. Thus, GRK6A is an essential regulatory component of NPT2A-dependent PTH-sensitive phosphate transport and corroborates previous findings that GRK6A pharmacological inhibitors abolish PTH action [ 44 ]. Binding affinities (3–5 µM) for the C-terminal PDZ ligand of GRK6A [ 63 ] or NPT2A (22 aa) [ 45 ] with NHERF1 are comparable and suggest that the binding mechanism is presumable identical.…”

Section: Npt2a-dependent Hormone-inhibitable Phosphate Transport Rsupporting

confidence: 91%

“…The relevance of Glu 43 and His 27 on NPT2A-dependent PTH-sensitive phosphate transport was validated by measuring phosphate uptake in OKH cells expressing the Glu 43 Asp/His 27 Asn-NHERF1 variant. As we presumed, Glu 43 Asp/His 27 Asn-NHERF1 blocks basal phosphate transport and is refractory to PTH [ 44 ]. Notably, when Asp 183 and Asn 167 in PDZ2 were replaced respectively by Glu and His, the corresponding residues in PDZ1, the Asp 183 Glu/Asn 167 His rescue variant bound the NPT2A C-terminal -TRL motif ( Figure 3 ) [ 45 ].…”

Section: Nherf1 (Pdz1) Specifically Binds Npt2a For Hormone-sensitmentioning

confidence: 99%

“…NPT2A and GRK6A interact with PDZ1 with a greater affinity than to PDZ2, thereby confirming that PDZ1 is naturally optimized to bind the -TRL sequence. Intriguingly, a minor interaction between GRK6A and PDZ2 is nonetheless critical for constitutive or PTH-induced phosphorylation of NHERF1 at Ser 290 [ 44 , 46 ], and for PTH-sensitive phosphate transport [ 44 ]. This finding highlights a biological puzzle as to how PDZ2 becomes accessible to GRK6A and the role of PTH and FGF23 in this process.…”

Section: Npt2a-dependent Hormone-inhibitable Phosphate Transport Rmentioning

confidence: 99%

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

Mamonova

Friedman

2021

IJMS

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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.

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Section: Npt2a-dependent Hormone-inhibitable Phosphate Transport Rsupporting

confidence: 91%

Section: Nherf1 (Pdz1) Specifically Binds Npt2a For Hormone-sensitmentioning

confidence: 99%

Section: Npt2a-dependent Hormone-inhibitable Phosphate Transport Rmentioning

confidence: 99%

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

Mamonova

Friedman

2021

IJMS

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“…Therefore, an important outcome of partially open states is different ligands have some access to both PDZ domains instead of relying on the complete release of autoinhibition by ezFERM binding. The dynamic mechanism offers a plausible explanation for why the PDZ2 domain is essential for phosphorylating Ser-290 in the C-terminal domain of WT NHERF1 (23,24).…”

Section: Structure Of Wildtype Nherf1 and Disease Variantsmentioning

confidence: 99%

“…Ezrin is indispensable for releasing autoinhibition, but phosphorylation plays an equally critical role in modulating the cellular activity of NHERF1 through its ability to oligomerize (20) and associate with various binding partners (10,21,22). In humans, NHERF1 is reversibly phosphorylated at Ser-290 by a multiprotein kinase cascade involving GRK6A, which in turn regulates PTH-sensitive, NPT2A (sodium-dependent phosphate transport protein 2A)-mediated phosphate uptake (23,24). Although GRK6A has much higher affinity for the N-terminal PDZ1 domain, it is through interactions with the partially masked PDZ2 domain that NHERF1 is phosphorylated in the C-terminal hinge region (20).…”

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confidence: 99%

Dynamic structure of the full-length scaffolding protein NHERF1 influences signaling complex assembly

Bhattacharya

Stanley

Heller

et al. 2019

Journal of Biological Chemistry

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The Na ؉ /H ؉ exchange regulatory cofactor 1 (NHERF1) protein modulates the assembly and intracellular trafficking of several transmembrane G protein-coupled receptors (GPCRs) and ion transport proteins with the membrane-cytoskeleton adapter protein ezrin. Here, we applied solution NMR and small-angle neutron scattering (SANS) to structurally characterize full-length NHERF1 and disease-associated variants that are implicated in impaired phosphate homeostasis. Using NMR, we mapped the modular architecture of NHERF1, which is composed of two structurally-independent PDZ domains that are connected by a flexible, disordered linker. We observed that the ultra-long and disordered C-terminal tail of NHERF1 has a type 1 PDZ-binding motif that interacts weakly with the proximal, second PDZ domain to form a dynamically autoinhibited structure. Using ensemble-optimized analysis of SANS data, we extracted the molecular size distribution of structures from the extensive conformational space sampled by the flexible chain. Our results revealed that NHERF1 is a diffuse ensemble of variable PDZ domain configurations and a disordered C-terminal tail. The joint NMR/SANS data analyses of three disease variants (L110V, R153Q, and E225K) revealed significant differences in the local PDZ domain structures and in the global conformations compared with the WT protein. Furthermore, we show that the substitutions affect the affinity and kinetics of NHERF1 binding to ezrin and to a C-terminal peptide from G protein-coupled receptor kinase 6A (GRK6A). These findings provide important insight into the modulation of the intrinsic flexibility of NHERF1 by disease-associated point mutations that alter the dynamic assembly of signaling complexes. Signal transduction in the biological milieu is a dynamic exchange of protein-protein interactions (1, 2), coordinated by a diverse family of scaffolding proteins (2-4). Structural mod-ularity of the scaffolds is fine-tuned for linking and transporting the different binding partners to the supramolecular signaling complexes. Well-known scaffold modules include Src homology 3, Src homology 2, PTB, WW, and the more abundant PDZ domains, which are ubiquitous for recruiting diverse protein targets (3, 4). As mediators of protein-protein interactions, PDZ domains have been shown to possess remarkable specificity for C-terminal binding motifs as well as internal peptide sequences of proteins (3). PDZ domains have emerged as key organizers of protein complexes at the plasma membrane, cytoplasmic tails of membrane proteins, and ion channels to promote their transport and localization to the cell surface for signaling (5). Full-length NHERF1 includes tandem PDZ domains, PDZ1 and PDZ2, and a C-terminal ezrin-binding domain (EBD) 4 juxtaposed with a PDZ-binding type 1 motif (Fig. 1). The EBD is a specific target of the FERM domain from ezrin (ezFERM), which disrupts the autoinhibition between the PDZ2 domain and the C-terminal tail in NHERF1 (6). Binding of ezrin with NHERF1 allosterically increases the PDZ domain ...

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Renal Contributions to Age‐Related Changes in Mineral Metabolism

2021

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Aging results in a general decline in function in most systems. This is particularly true with respect to the skeleton and renal systems, impacting mineral homeostasis. Calcium and phosphate regulation requires tight coordination among the intestine, bone, parathyroid gland, and kidney.The role of the intestine is to absorb calcium and phosphate from the diet. The bone stores or releases calcium and phosphate depending on the body's needs. In response to low plasma ionized calcium concentration, the parathyroid gland produces parathyroid hormone which modulates bone turnover. The kidney reabsorbs or excretes the minerals and serves as the final regulator of plasma concentration. Many hormones are involved in this process in addition to parathyroid hormone, including fibroblast growth factor 23 produced by the bone, and calcitriol synthesized by the kidney. Sclerostin, calcitonin, osteoprotegerin and receptor activator of nuclear factor κ-B ligand also contribute to tissue-specific regulation. Changes in the function of organs due to aging or disease can perturb this balance. During aging, the intestine cannot absorb calcium efficiently due to decreased expression of key proteins. In the bone, the balance between bone formation and bone resorption tends toward the latter in older individuals. The kidney may not filter blood as efficiently in the later decades of life and the expression of certain proteins necessary for mineral homeostasis declines with age. These changes often lead to dysregulation of organismal mineral homeostasis. This review will focus on how mineral homeostasis is impacted by aging with a particular emphasis on the kidney's role in this process.

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Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport

Cited by 26 publications

References 105 publications

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

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

Dynamic structure of the full-length scaffolding protein NHERF1 influences signaling complex assembly

Renal Contributions to Age‐Related Changes in Mineral Metabolism

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