The scaffold protein PDZK1 undergoes a head-to-tail intramolecular association that negatively regulates its interaction with EBP50.
PDZK1 (also known as CAP70, NHERF3, or NaPi-Cap1) is a scaffolding protein composed of four PDZ (Post-Synaptic Density-95, Discs Large, Zonula Occludens-1) domains followed by a short carboxyl-terminal tail. This scaffold acts as a mediator of localization and expression levels of multiple receptors in the kidney, liver, and endothelium. Here, we characterize the self-association properties of the protein. PDZK1 can undergo modest homodimerization in vivo and in vitro through self-association involving its third PDZ domain. In addition, the tail of PDZK1 interacts in an intramolecular fashion with the first PDZ domain, but this interaction does not contribute to dimer formation. The interaction between the tail of PDZK1 and its first PDZ domain induces the protein to adopt a more compact conformation. A head-to-tail association has also been reported for EBP50/NHERF1, a two-PDZ domain member of the same scaffolding protein family as PDZK1, and shown to regulate binding of target proteins to the EBP50 PDZ domains. As opposed to EBP50, the association of PDZK1 with specific ligands for its PDZ domains is unaffected by the intramolecular association, establishing a different mode of interaction among these two members of the same scaffolding family. However, the tail of PDZK1 interacts with the PDZ domains of EBP50, and this interaction is negatively regulated by the intramolecular association of PDZK1. Thus, we have uncovered a regulated association between the two PDZ-containing scaffolding molecules, PDZK1 and EBP50.
LaLonde
David P
DP
Weill Institute for Cell and Molecular Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.
Bretscher
Anthony
A
D019943:Amino Acid Substitution / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins; D008958:Models, Molecular; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027981:Symporters; D014162:Transfection
D002352:Carrier Proteins; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C484659:PDZK1 protein, human; D010446:Peptide Fragments; D010750:Phosphoproteins; D011994:Recombinant Proteins; C109807:SLC22A4 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters; C093376:sodium-hydrogen exchanger regulatory factor