Alternative titles; symbols
HGNC Approved Gene Symbol: PDZK1
Cytogenetic location: 1q21.1 Genomic coordinates (GRCh38) : 1:145,670,852-145,707,400 (from NCBI)
Custer et al. (1997) cloned a gene from rat kidney mRNA that encodes a protein regulated by dietary phosphate. They designated the protein Diphor-1 (dietary P(i)-regulated RNA-1) and found that it shares homology with the PDZ domain-containing protein Na+/H+ exchanger regulatory factor.
White et al. (1998) showed that human PDZK1, a PDZ domain-containing protein highly homologous to rat Diphor-1, is expressed in human kidney.
By PCR analysis of a human/rodent somatic cell hybrid mapping panel and by radiation hybrid analysis, White et al. (1998) mapped the PDZK1 gene to chromosome 1q21.
Custer et al. (1997) demonstrated that rat Diphor-1 specifically increased Na(+)-dependent phosphate uptake by 1.7 times when coexpressed in Xenopus laevis oocytes with the Na(+)-P(i) cotransporter, indicating that it may play an important role in cellular phosphate regulation. Diphor-1 mRNA expression was upregulated several fold by a restricted phosphate diet, highlighting the possible role of the protein in maintaining overall phosphate homeostasis.
Using the yeast 2-hybrid system, Kocher et al. (1998) identified PDZK1 as a protein interacting with MAP17 (607178), a 17-kD membrane-associated protein. By in situ hybridization, they showed that both proteins are upregulated in human carcinomas arising in kidney, lung, colon, and breast. Using the yeast 2-hybrid system, Kocher et al. (1999) found that PDZK1 interacts with CMOAT (ABCC2; 601107), a canalicular multispecific organic anion transporter involved in multidrug resistance. The finding was considered of particular interest because proteins containing PDZ domains are involved in the clustering and signaling pathways of membrane-associated proteins, including ion channels. Therefore, the protein cluster formed by the association of CMOAT, PDZK1, and MAP17 could play an important role in the cellular mechanisms associated with multidrug resistance, and PDZK1 may represent a new target in cancer cells resistant to chemotherapeutic agents.
The scavenger receptor class B type I (SRBI, or SCARB1; 601040) mediates the selective uptake of cholesteryl esters from high density lipoprotein and cholesterol secretion into bile in the liver. Ikemoto et al. (2000) identified an SRBI-associated protein (PDZK1) from rat liver membrane extracts by using an affinity chromatography technique. The 523-amino acid protein contains 4 PDZ domains and associates with the C terminus of SRBI using its N-terminal first PDZ domain. Ikemoto et al. (2000) designated th protein CLAMP (C-terminal linking and modulating protein). CLAMP was located mostly in the sinusoidal membranes, whereas SRBI was detected in both sinusoidal and canalicular membranes. After the solubilization of the liver membranes with Triton X-100, SRBI was immunoprecipitated with anti-CLAMP monoclonal antibody, suggesting the association of these proteins in vivo. By coexpressing SRBI with CLAMP in CHO cells, Ikemoto et al. (2000) observed an increase in the expression level of SRBI, a reduction in the deacylation rate of the cholesteryl esters taken up from HDL, and a change in the intracellular distribution of a fluorescent lipid taken up from HDL. The data suggested that CLAMP is associated with SRBI in the liver sinusoidal plasma membranes and may modulate intracellular transport and metabolism of cholesteryl esters taken up from HDL.
Wang et al. (2000) identified a hydrophilic CFTR (602421)-binding protein, CAP70, which is also concentrated on the apical surfaces. CAP70 had previously been identified by Kocher et al. (1998) as PDZK1. The protein contains 4 PDZ domains, 3 of which are capable of binding to the C terminus of CFTR. Linking at least 2 CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein.
Using in vitro pull-down assays, Thomson et al. (2005) determined that human PDZK1 interacted with the sodium-hydrogen exchanger Nhe3 (SLC9A3; 182307) and the chloride-anion exchanger Cfex (SLC26A6) in rabbit renal brush border membrane vesicles. The interactions were mediated via the C-terminal PDZ-binding domains of Nhe3 and Cfex. Using Pdzk1-null mice, Thomson et al. (2005) determined that brush border expression of Nhe3 was unaffected by loss of Pdzk1, but expression of Cfex was markedly reduced. Functional activity of Cfex was also dramatically reduced in Pdzk1-null mice.
PDZ domains are central organizers of protein complexes at the plasma membrane. Fanning and Anderson (1999) reviewed general concepts concerning their biology. These included the structural basis for specificity of their binding interactions and ideas about how they organize both small local protein complexes used for signal transduction (transducisomes) and larger 2-dimensional complexes like cell junctions and plasma membrane domains. PDZ domains were originally identified as conserved sequence elements within the postsynaptic density protein PSD95 (602887), the Drosophila tumor suppressor dlg-A (600723), and the tight junction protein ZO1 (601009). PDZ is an acronym derived from these first 3 PDZ-containing proteins: PDS95/DLG/ZO1. Fanning and Anderson (1999) stated that these 80- to 90-amino acid sequences had been identified in more than 75 proteins and were characteristically expressed in multiple copies within a single protein. They have a broad species distribution and the overwhelming majority of proteins containing them are associated with the plasma membrane. Although PDZ domains are found in many different structures, each PDZ protein is generally restricted to specific subcellular domains, such as synapses; cell-cell contacts; or the apical, basal, or lateral cell surface. This led to the speculation that PDZ domains evolved early to play a central role in the organization of the plasma membrane domains.
Kocher et al. (2003) developed Pdzk1 null mice. Mutant mice developed normally, had no gross phenotypic abnormalities, and were fecund. Lack of Pdzk1 altered the expression of selective ion channels in the kidney and increased serum cholesterol levels. No significant redistribution of proteins known to interact with Pdzk1, such as Map17, cmoat, and the type IIa Na/Pi cotransporter, was observed. Kocher et al. (2003) concluded that the lack of significant phenotype in Pdzk1-deficient mice may be due to functional compensation by other Pdz domain-containing proteins.
Custer, M., Spindler, B., Verrey, F., Murer, H., Biber, J. Identification of a new gene product (diphor-1) regulated by dietary phosphate. Am. J. Physiol. 273: F801-F806, 1997. [PubMed: 9374845] [Full Text: https://doi.org/10.1152/ajprenal.1997.273.5.F801]
Fanning, A. S., Anderson, J. M. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J. Clin. Invest. 103: 767-772, 1999. [PubMed: 10079096] [Full Text: https://doi.org/10.1172/JCI6509]
Ikemoto, M., Arai, H., Feng, D., Tanaka, K., Aoki, J., Dohmae, N., Takio, K., Adachi, H., Tsujimoto, M., Inoue, K. Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I. Proc. Nat. Acad. Sci. 97: 6538-6543, 2000. [PubMed: 10829064] [Full Text: https://doi.org/10.1073/pnas.100114397]
Kocher, O., Comella, N., Gilchrist, A., Pal, R., Tognazzi, K., Brown, L. F., Knoll, J. H. M. PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein. Lab. Invest. 79: 1161-1170, 1999. [PubMed: 10496535]
Kocher, O., Comella, N., Tognazzi, K., Brown, L. F. Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains. Lab. Invest. 78: 117-125, 1998. [PubMed: 9461128]
Kocher, O., Pal, R., Roberts, M., Cirovic, C., Gilchrist, A. Targeted disruption of the PDZK1 gene by homologous recombination. Molec. Cell. Biol. 23: 1175-1180, 2003. [PubMed: 12556478] [Full Text: https://doi.org/10.1128/MCB.23.4.1175-1180.2003]
Thomson, R. B., Wang, T., Thomson, B. R., Tarrats, L., Girardi, A., Mentone, S., Soleimani, M., Kocher, O., Aronson, P. S. Role of PDZK1 in membrane expression of renal brush border ion exchangers. Proc. Nat. Acad. Sci. 102: 13331-13336, 2005. [PubMed: 16141316] [Full Text: https://doi.org/10.1073/pnas.0506578102]
Wang, S., Yue, H., Derin, R. B., Guggino, W. B., Li, M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell 103: 169-179, 2000. [PubMed: 11051556] [Full Text: https://doi.org/10.1016/s0092-8674(00)00096-9]
White, K. E., Biber, J., Murer, H., Econs, M. J. A PDZ domain-containing protein with homology to Diphor-1 maps to human chromosome 1q21. Ann. Hum. Genet. 62: 287-290, 1998. [PubMed: 9924606] [Full Text: https://doi.org/10.1046/j.1469-1809.1998.6240287.x]