Lysosome-associated protein transmembrane 4α (LAPTM4α) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes

Lysosome-associated protein transmembrane 4alpha (LAPTM4alpha) and homologues comprise a family of conserved proteins, which are found in mammals, insects and nematodes. LAPTM4alpha functions to regulate the intracellular compartmentalization of amphipathic solutes and possibly the sensitivity of cells toward anthracyclines, antibiotics, ionophores, nucleobases and organic cations. This is similar to the multidrug-resistance phenotype exhibited by cells synthesizing high levels of beta-glycoprotein. Accordingly, it is possible that LAPTM4alpha may be a suitable target for development of novel chemotherapeutic agents. LAPTM4alpha contains four putative membrane-spanning domains and a 55 amino acid C-terminal region that faces the cytoplasm. Localization of LAPTM4alpha to endosomes and lysosomes appears to be tightly controlled as transient high-level expression of LAPTM4alpha in cultured cells resulted in no detectable protein on the cell surface. Mutagenic analysis of the C-terminus of LAPTM4alpha indicated that two tandomly arranged tyrosine-containing motifs in the cytoplasmic domain are required for efficient localization of LAPTM4alpha to vesicles containing the lysosomal marker lysosomal glycoprotein 120. Although a number of membrane proteins that localize to endosomes/lysosomes contain more than one independently functioning sorting signal, to our knowledge, LAPTM4alpha is the first example of a membrane protein that requires two tandemly arranged tyrosine-based sorting signals for efficient localization in these compartments.