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Molecular analysis of the interaction between the prostacyclin receptor and the first PDZ domain of PDZK1Molecular analysis of the interaction between the prostacyclin receptor and the first PDZ domain of PDZK1
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] Publication Abstract from PubMedThe prostanoid prostacyclin, or prostaglandin I, plays an essential role in many aspects of cardiovascular disease. The actions of prostacyclin are mainly mediated through its activation of the prostacyclin receptor or, in short, the IP. In recent studies, the cytoplasmic carboxy-terminal domain of the IP was shown to bind several PDZ domains of the multi-PDZ adaptor PDZK1. The interaction between the two proteins was found to enhance cell surface expression of the IP and to be functionally important in promoting prostacyclin-induced endothelial cell migration and angiogenesis. To investigate the interaction of the IP with the first PDZ domain (PDZ1) of PDZK1, we generated a nine residue peptide (KKIAACSLC) containing the seven carboxy-terminal amino acids of the IP and measured its binding affinity to a recombinant protein corresponding to PDZ1 by isothermal titration calorimetry. We determined that the IP interacts with PDZ1 with a binding affinity of 8.2 microM. Using the same technique, we also determined that the farnesylated form of carboxy-terminus of the IP does not bind to PDZ1. To understand the molecular basis of these findings, we solved the high resolution crystal structure of PDZ1 bound to a 7-residue peptide derived from the carboxy-terminus of the non-farnesylated form of IP (IAACSLC). Analysis of the structure demonstrates a critical role for the three carboxy-terminal amino acids in establishing a strong interaction with PDZ1 and explains the inability of the farnesylated form of IP to interact with the PDZ1 domain of PDZK1 at least . Molecular Analysis of the Prostacyclin Receptor's Interaction with the PDZ1 Domain of Its Adaptor Protein PDZK1.,Birrane G, Mulvaney EP, Pal R, Kinsella BT, Kocher O PLoS One. 2013;8(2):e53819. doi: 10.1371/journal.pone.0053819. Epub 2013 Feb 6. PMID:23457445[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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