TIP-1 has PDZ scaffold antagonist activity.
PDZ proteins usually contain multiple protein-protein interaction domains and act as molecular scaffolds that are important for the generation and maintenance of cell polarity and cell signaling. Here, we identify and characterize TIP-1 as an atypical PDZ protein that is composed almost entirely of a single PDZ domain and functions as a negative regulator of PDZ-based scaffolding. We found that TIP-1 competes with the basolateral membrane mLin-7/CASK complex for interaction with the potassium channel Kir 2.3 in model renal epithelia. Consequently, polarized plasma membrane expression of Kir 2.3 is disrupted resulting in pronounced endosomal targeting of the channel, similar to the phenotype observed for mutant Kir 2.3 channels lacking the PDZ-binding motif. TIP-1 is ubiquitously expressed, raising the possibility that TIP-1 may play a similar role in regulating the expression of other membrane proteins containing a type I PDZ ligand.
Alewine
Christine
C
Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Olsen
Olav
O
Wade
James B
JB
Welling
Paul A
PA
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D016764:Cell Polarity; D002522:Chlorocebus aethiops; D004285:Dogs; D005972:Glutaminase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008957:Models, Genetic; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D013329:Structure-Activity Relationship; D014162:Transfection; D020798:Two-Hybrid System Techniques
D047908:Intracellular Signaling Peptides and Proteins; C119588:LIN-7 protein, mammalian; D008565:Membrane Proteins; D024661:Potassium Channels, Inwardly Rectifying; C421249:TAX1BP3 protein, human; D005972:Glutaminase