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Friedman Lab

 

Studies in Dr. Friedman's laboratory focus primarily on the mechanism and regulation of calcium transport across cell membranes. Experimental work is presently directed toward characterizing the interactions between the calcium-sensing receptor (CaSR) and parathyroid hormone (PTH) on calcium absorption by renal thick ascending limbs and distal tubule cells.

Problems under investigation include: 1) delineating the role of the CaSR in controlling basal and PTH-dependent calcium absorption; 2) determining the role of calcium channel subunits in regulating distal tubule calcium absorption; and, 3) defining structural elements in the PTH receptor responsible for signaling and internalization.

Techniques applied to these studies include cell culture models, isolated perfused single tubules, and clearance studies in transgenic mice. Single cell fluorescence, tracer flux measurements, heterologous receptor expression, antisense depletion techniques, biochemical and molecular analyses of second messenger formation are routinely applied. Elucidation of the mechanism of PTH receptor signaling will not only explain the physiological action of PTH at one of its principal target sites but also provide insight into novel mechanisms by which cell specific signaling is conferred. The resulting information will be valuable in understanding mineral ion homeostasis under normal conditions, as well as disordered calcium balance in renal failure, hyperparathyroidism, or osteoporosis. The results will provide insights into analogs that may be candidates for selective therapeutic applications.

Peter A. Friedman, PhD

Complete NCBI Publications

PDZ proteins and mineral-ion homeostasis
 
Our lab focuses on the biochemistry underlying the regulatory mechanisms by which PDZ proteins such as NHERF1 and Scribble legislate PTH and FGF23 actions on signaling and the function of membrane receptors and transporters for phosphate and calcium. The overall goal of our work is to dissect the mechanism by which the NHERF1 PDZ protein platform integrates discrete but convergent signaling by the PTH receptor, a GPCR, and FGFR1, a structurally unrelated receptor tyrosine kinase to regulate NPT2A-mediated phosphate transport. A major thrust of the work is to characterize a cryptic internal PDZ ligand in NPT2A, which we advance as the hormone-sensitive control element associated with phosphate wasting in reported mutations. We are especially interested in characterizing the role of phosphorylation in dissembling the NPT2A-NHERF1-RGS14 complex, a vital step in hormone-regulated phosphate transport. We apply a combination of classical research tools, including cell-free and cell-based systems, molecular dynamics modeling, and state-of-the-art structural biological approaches.




 
Headshot of Peter A. Friedman, PhD
Peter A. Friedman, PhD
Professor

Peter A. Friedman, PhD

Journal Articles

Sneddon WB, Friedman PA, and Mamonova T. Mutations in an unrecognized internal NPT2A PDZ motif disrupt phosphate transport and cause congenital hypophosphatemia. Biochem J 480: 685–699, 2023.
 
Stewart BZ, Mamonova T, Sneddon WB, Javorsky A, Yang Y, Wang B, Nolin TD, Humbert PO, Friedman PA and Kvansakul M. Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis. Proc Natl Acad Sci USA 120: e2220851120, 2023.
Friedman PA, Sneddon WB, Mamonova T, Montanez-Miranda C, Ramineni S, Harbin NH, Squires KE, Gefter JV, Magyar CE, Emlet DR, and Hepler JR. RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein. J Biol Chem 298:101836, 2022.
Vistrup-Parry M, Sneddon WB, Bach S, Stromgaard K, Friedman PA and Mamonova T. Multisite NHERF1 phosphorylation controls GRK6A regulation of hormone-sensitive phosphate transport. J Biol Chem 296: 100473, 2021.
Zhang Q, Gefter J, Sneddon WB, Mamonova T and Friedman PA. ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. iScience 24: 102770, 2021.
Mamonova T and Friedman PA. Noncanonical sequences involving NHERF1 interaction with NPT2A govern hormone-regulated phosphate transport: binding outside the box. Int J Med Sci 22: 1087, 2021.
 
Zhang Q and Friedman PA. Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications. Int J Mol Sci 22: 10963, 2021.

Tatyana Mamonova, PhD

Journal Articles

Mamonova T, M Kurnikova and PA Friedman.  Structural basis for NHERF1 PDZ domain binding.  Biochemistry 51:3110-3120, 2012.
Mamonova T, AV Glyakina, MG Kurnikova and OV Galzitskaya.  Flexibility and mobility in mesophilic and thermophilic homologus proteins from molecular dynamics and fold unfold method.  J Bioinfo Comput Biology 8:1-18, 2010.
Mamonova T, K Speranskiy and M Kurnikova.  Interplay between structural rigidity and electrostatic interactions in the ligand binding domain of GluR2.  Proteins: Structure, Function and Bioinformatics 73:656-671, 2008.
Mamonova T, K Speranskiy and M Kurnikova.  Interplay between structural rigidity and electrostatic interations in the ligand binding domain of GluR2.  Proteins:  Structure, Function and Bioinformatics 73:656-671, 2008.
Mamonova T and M Kurnikova.  Structure and energetic of channel forming protein-polysaccaride complexes.  J Phys Chem 110:25091-25100, 2006.