This represents a departure from the classic PDZ protein retention/clustering scheme because PDZ proteins rely on multiple protein–protein interaction motifs to effectively scaffold membrane, cytoskeletal, and signaling proteins. Here, we show that the full-length TIP-1 encodes a protein consisting of a single PDZ domain and appears to be devoid of other protein–protein interaction modules. A partial TIP-1 clone was originally identified through a yeast two-hybrid screen as one of many binding partners for the viral oncoprotein Tax ( Rousset et al., 1998). While investigating the mechanism for polarized expression of Kir 2.3, we discovered a novel PDZ-binding partner for the channel, Tax-interacting Protein-1 (TIP-1). The mLin-7/CASK complex has also been implicated in basolateral expression of the epithelial GABA transporter BGT-1 ( Perego et al., 1999), the EGF-like receptor ErbB-2/Her2 ( Shelly et al., 2003), and other potassium channels ( Leonoudakis et al., 2004b), suggesting that interaction with the mLin-7/CASK complex represents a general mechanism for the polarized expression of basolateral membrane proteins containing a PDZ-binding motif. Recently, we demonstrated that mLin-7 binds the inwardly rectifying potassium channel Kir 2.3 through a PDZ interaction and that the mLin-7/CASK complex plays an important role in coordinating polarized expression of the channel at the basolateral membrane by preventing the channel from traveling in the endocytic pathway ( Olsen et al., 2002). Although renal epithelia do not express a Lin-10 orthologue ( Borg et al., 1998), the mLin-7 and CASK complex is evolutionarily conserved and localizes exclusively at the basolateral membrane ( Olsen et al., 2005 Straight et al., 2001). elegans PDZ protein complex have been identified in mammalian tissues ( Borg et al., 1998 Butz et al., 1998 Straight et al., 2001b Olsen et al., 2002). elegans, depletion of any one of these three PDZ proteins causes mislocalization of Let-23 to the apical membrane, illustrating the functional significance of the complex. The smaller Lin-7 protein acts as the bridge between receptor and scaffold complex, binding the receptor through a type I PDZ interaction and the scaffold via a L27 domain interaction ( Doerks et al., 2000) with CASK ( Kaech et al., 1998). Lin-10 offers a means of delivering the complex via its interactions with microtubule motors ( Setou et al., 2000) and Munc-18 docking machinery ( Hata et al., 1993 Borg et al., 1998 Butz et al., 1998). Lin-2 (CASK) interacts with cell structural elements, anchoring the complex to the membrane ( Cohen et al., 1998). elegans and mammalian systems have revealed a probable mechanism. In vulvar precursor cells, these molecules form a tripartite protein complex that interacts with the Let-23 receptor to coordinate its expression on the basolateral membrane ( Simske et al., 1996 Kaech et al., 1998 Rongo et al., 1998). A prototypical example is provided by a group of PDZ proteins, Lin-7 (mLin-7/Veli/MALS), Lin-2 (CASK) and Lin10 (Mint-1/X11), that were first discovered in Caenorhabditis elegans ( Kaech et al., 1998). ![]() Many play important roles in the generation and maintenance of epithelial and neuronal polarity. ![]() PDZ proteins are generally characterized by the presence of multiple protein–protein interaction modules, which allows them to act as molecular scaffolds that recruit membrane proteins, cytoskeletal elements, trafficking machinery, and signal transduction molecules into multimeric complexes at distinct membrane domains ( Brone and Eggermont, 2005 Campo et al., 2005).
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