IDENTIFICATION OF AN EVOLUTIONARILY CONSERVED HETEROTRIMERIC PROTEIN COMPLEX INVOLVED IN PROTEIN TARGETING

In Caenorhabditis elegans, lin-2, lin-7, and lin-IO genetically intera ct to control the trafficking of the Let-23 growth factor receptor to the basolateral surface of body epithelia. The human homologue of the lin-10 gene has recently been identified as a member of the X11 gene f amily. The X11 proteins contain one phosphotyrosine binding (PTB) and two PSD-95.Dlg.ZO-1 (PDZ) domains as well as an extended amino terminu s. We have previously shown that the PTB domain of X11 alpha (also kno wn as Mint1) can bind to the amyloid precursor protein (APP) in a phos photyrosine-independent fashion and can markedly inhibit the processin g of APP to the amyloid beta (A beta) peptide. Here, we report that X1 1 alpha directly binds to the mammalian homologue of Lin-2 (mLin-2), a lso known as CASK. This binding is mediated by direct interaction betw een the Calmodulin Kinase II (CKII)-like domain of mLin-2 and the amin o terminus of X11 alpha. Furthermore, we can detect direct interaction s between mLin-2 and mammalian Lin-7 (mLin-7). In mouse brain, we have identified a heterotrimeric complex that contains mLin-2, mLin-7, and X11 alpha and that is likely important for the localization of protei ns in polarized cells. This complex may play an important role in the trafficking and processing of APP in neurons.