Recent advances in the targeting and functional diversity of LAMP-2 short tail variants

LAMP2 is one of the major lysosomal membrane proteins. It contains a large luminal domain, a single transmembrane (TM) domain, and an unusually short cytoplasmic tail composed of only 11 amino acids. Three splicing variants-LAMP-2A, LAMP-2B, and LAMP-2C-share an identical luminal domain but differ in their TM and cytoplasmic tail sequences, resulting in distinct trafficking pathways and functions. Yamaguchi et al. demonstrated that the ultimate target compartments of these isoforms diverge according to the binding affinities of their cytoplasmic tails for μ-subunits of adaptor protein (AP) complexes AP-1, AP-2, AP-3, and AP-4. Intriguingly, each isoform contributes to specific lysosomal functions. It is remarkable that such short cytoplasmic tails not only determine subcellular localization but also underlie the functional diversity of LAMP-2 isoforms.