| Structural highlights
Function
[NHRF3_MOUSE] 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 (By similarity). May be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys(14)-Xaa(4)-Asn(19)-Tyr-Gly-Phe-Phe-Leu(24)), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI ((503)VLQEAKL(509)). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (K(d)) of the K14A and F22A mutants were 3.2 and 4.0 muM, respectively, similar to 2.6 muM measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI ((505)QEAKL(509)) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10-20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1.
In vitro and in vivo analysis of the binding of the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), to the PDZ1 domain of its adaptor protein PDZK1.,Kocher O, Birrane G, Tsukamoto K, Fenske S, Yesilaltay A, Pal R, Daniels K, Ladias JA, Krieger M J Biol Chem. 2010 Nov 5;285(45):34999-5010. Epub 2010 Aug 25. PMID:20739281[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang S, Yue H, Derin RB, Guggino WB, Li M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell. 2000 Sep 29;103(1):169-79. PMID:11051556
- ↑ Kocher O, Pal R, Roberts M, Cirovic C, Gilchrist A. Targeted disruption of the PDZK1 gene by homologous recombination. Mol Cell Biol. 2003 Feb;23(4):1175-80. PMID:12556478
- ↑ Gisler SM, Pribanic S, Bacic D, Forrer P, Gantenbein A, Sabourin LA, Tsuji A, Zhao ZS, Manser E, Biber J, Murer H. PDZK1: I. a major scaffolder in brush borders of proximal tubular cells. Kidney Int. 2003 Nov;64(5):1733-45. PMID:14531806 doi:10.1046/j.1523-1755.2003.00266.x
- ↑ Kato Y, Sai Y, Yoshida K, Watanabe C, Hirata T, Tsuji A. PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2. Mol Pharmacol. 2005 Mar;67(3):734-43. Epub 2004 Nov 2. PMID:15523054 doi:mol.104.002212
- ↑ Kocher O, Birrane G, Tsukamoto K, Fenske S, Yesilaltay A, Pal R, Daniels K, Ladias JA, Krieger M. In vitro and in vivo analysis of the binding of the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), to the PDZ1 domain of its adaptor protein PDZK1. J Biol Chem. 2010 Nov 5;285(45):34999-5010. Epub 2010 Aug 25. PMID:20739281 doi:10.1074/jbc.M110.164418
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