4F8K

Molecular analysis of the interaction between the prostacyclin receptor and the first PDZ domain of PDZK1

Summary for 4F8K

• Entry DOI: 10.2210/pdb4f8k/pdb
• Related: 3NGH
• Descriptor: Na(+)/H(+) exchange regulatory cofactor NHE-RF3, Prostacyclin receptor (2 entities in total)
• Functional Keywords: pdz domain, adaptor protein, prostacyclin receptor, chimera protein, fusion protein, signaling protein
• Biological source: Mus musculus (mouse); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P43252
• Total number of polymer chains: 2
• Total formula weight: 24033.07

Authors

Kocher, O.,Birrane, G.,Kinsella, B.T.,Mulvaney, E.P. (deposition date: 2012-05-17, release date: 2013-02-27, Last modification date: 2023-09-13)

Primary citation

Birrane, G.,Mulvaney, E.P.,Pal, R.,Kinsella, B.T.,Kocher, O.
Molecular Analysis of the Prostacyclin Receptor's Interaction with the PDZ1 Domain of Its Adaptor Protein PDZK1.
Plos One, 8:e53819-e53819, 2013

PubMed Abstract: The prostanoid prostacyclin, or prostaglandin I2, 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 (KK(411)IAACSLC(417)) 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 µM. 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 ((411)IAACSLC(417)). 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 in vitro.

PubMed: 23457445
DOI: 10.1371/journal.pone.0053819

Experimental method

X-RAY DIFFRACTION (1.7 Å)