Guarnieri F G, Arterburn L M, Penno M B, Cha Y, August J T
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J Biol Chem. 1993 Jan 25;268(3):1941-6.
We have investigated the mechanism by which LAMP-1, a principal protein of the lysosomal membrane, is targeted to lysosomes. Mutagenesis and transfection experiments indicate that the motif Tyr-X-X-hydrophobic residue at the carboxyl terminus of the 11-amino acid cytoplasmic tail of the protein constitutes the lysosomal targeting signal for LAMP-1. This motif directs CD44, a cell surface hyaluronate receptor, to the lysosomal membrane, but only when the signal is placed at the carboxyl-terminus of a truncated cytoplasmic tail. The signal did not confer lysosomal targeting when it was situated internally or at the carboxyl terminus of the normal CD44 cytoplasmic tail. An apparent paradox is that similar Tyr-containing sequences mediate internalization, but not lysosomal targeting, of several receptors. Of possible relevance is the additional finding that purified LAMP-1 protein lacks the two carboxyl-terminal residues predicted by cDNA, both of which are essential for proper trafficking. A model is proposed in which lysosomal targeting is distinguished from receptor internalization through proteolytic modification of the internalization signal.
我们研究了溶酶体膜主要蛋白LAMP-1靶向溶酶体的机制。诱变和转染实验表明，该蛋白11个氨基酸的细胞质尾部羧基末端的基序Tyr-X-X-疏水残基构成了LAMP-1的溶酶体靶向信号。此基序可将细胞表面透明质酸受体CD44导向溶酶体膜，但前提是该信号位于截短细胞质尾部的羧基末端。当该信号位于正常CD44细胞质尾部内部或羧基末端时，不会赋予溶酶体靶向性。一个明显的矛盾是，类似的含酪氨酸序列介导几种受体的内化，但不介导溶酶体靶向。一个可能相关的额外发现是，纯化的LAMP-1蛋白缺少cDNA预测的两个羧基末端残基，这两个残基对于正确的运输都是必不可少的。我们提出了一个模型，其中溶酶体靶向通过内化信号的蛋白水解修饰与受体内化区分开来。
