![]() Hrs/Vps27 binds to Vps23/TSG101 (the mammalian orthologue of Vps23) via the P(S/T)AP motif ( Bache et al., 2003 Bilodeau et al., 2003 Lu et al., 2003 Pornillos et al., 2003). Mutation of the Hrs UIM domain abrogates its ability to bind to ubiquitylated proteins ( Bishop et al., 2002) and consequently prevents ubiquitylated cargo proteins from being sorted into the vacuole lumen ( Shih et al., 2002). ![]() ![]() Hrs and Vps27, a yeast orthologue of Hrs, bind to ubiquitin ( Lloyd et al., 2002 Polo et al., 2002 Raiborg et al., 2002). Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) was identified as a phosphotyrosine protein after stimulation with hepatocyte growth factor ( Komada and Kitamura, 1995). Taken together, these results indicate that precise sorting of IL-2Rβ from early to late endosomes is mediated by Hrs, a known sorting component of the ubiquitin-dependent machinery, in a manner that is independent of UIM-ubiquitin binding. The latter mutant exhibits attenuated degradation. By contrast, an IL-2Rβ mutant lacking the Hrs-binding region passes through early endosomes and is mis-sorted to compartments positive for the transferrin receptor. Trafficking and degradation assays revealed that, similarly to wild-type IL-2Rβ, an IL-2Rβ mutant lacking all the cytoplasmic lysine residues is sorted from Hrs-positive early endosomes to LAMP1-positive late endosomes, resulting in degradation of the receptor. We found a direct interaction between bacterially expressed IL-2Rβ and Hrs in GST pull-down assays, indicating that their binding is independent of ubiquitin. Here, we show that the C-terminal region of Hrs, which does not contain the UIM domain, can bind to interleukin-2 receptor β (IL-2Rβ). The hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) interacts with ubiquitylated cargoes through its ubiquitin-interacting-motif domain (UIM domain), and plays an essential early role in endosomal sorting. ![]() Several lines of evidence have revealed that ubiquitylation of membrane proteins serves as a signal for endosomal sorting into lysosomes or lytic vacuoles. ![]()
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