9rxs
Structure of the PDZ4 domain from human PDZK1 (NHERF3) with the C-terminal residues (VLKSTQF) of human URAT1 transporter (SLC22A12)
Structural highlights
DiseaseS22AC_HUMAN Hereditary renal hypouricemia. The disease is caused by variants affecting the gene represented in this entry. FunctionS22AC_HUMAN Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:12024214, PubMed:22194875, PubMed:35144162, PubMed:35462902). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:12024214, PubMed:22194875). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:12024214). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (PubMed:12024214). Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption (PubMed:21350910). Orotate transport is Cl(-)-dependent (PubMed:21350910).[1] [2] [3] [4] [5] NHRF3_HUMAN A scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. May be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with SLC9A3R1, may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. May play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. May function to connect SCARB1 with the cellular machineries for intracellular cholesterol transport and/or metabolism. May be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (By similarity). Publication Abstract from PubMedThe renal solute carrier URAT1 (SLC22A12) is essential for urate homeostasis, with loss-of-function linked to renal hypouricemia, nephrolithiasis and lower gout risk. URAT1 function depends on binding the multi-PDZ domain scaffold protein PDZK1 (NHERF3), with a similar role suggested for the related NHERF1. The molecular basis of these interactions remains poorly understood. Using fluorescence anisotropy, we show that full-length human PDZK1 binds the C-terminal peptide of URAT1 with high affinity (K(D) 170 nM), unlike NHERF1 (K(D) >70 microM). The PDZ1 domain of PDZK1 alone is sufficient for high-affinity binding (K(D) 160 nM), while PDZ4 provides a secondary site (K(D) 1.35 microM), with both interactions characterized by rapid kinetics. Gel filtration shows that PDZK1 can bind two URAT1 peptides. X-ray structures of individual PDZ domains from PDZK1 and NHERF1 complexed with the URAT1 peptide reveal the underlying molecular basis for selectivity and broad affinity range. Murine Pdzk1 and Nherf1 bind Urat1 with high affinity indicating species-specific interactions. These data provide insights into URAT1 regulation by PDZ scaffold proteins with relevance for understanding urate homeostasis regulation and related disorders. Molecular determinants of selective and high-affinity binding of the scaffold protein PDZK1 to the urate transporter URAT1.,Mymrikov EV, Wirth C, Heinicke JI, Goll J, Kern BA, Steck C, Iaroslavtceva AK, Muhlethaler T, Kottgen A, Hunte C J Mol Biol. 2025 Dec 24:169615. doi: 10.1016/j.jmb.2025.169615. PMID:41453723[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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