Lysosome-targeting signals

Metcalf, P., and Fusek, M. (1993). Two crystal structure for cathepsin D The lysosomal targeting signal and active site. EMBO J. 12, 1293-1302. 

Piguet, V., Gu, F., Foti, M., Demaurex, N., Gruenberg, J.-L. and Carpentier, J, and Trono, D. (1999). Nef-induced CD4 degradation a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of /3-COP in endosomes. Cell 97, 63-73. 

The I-cell patient has proved invaluable for elucidation of the complex nature of intracellular packaging and sorting of lysosomal enzymes. The physiological importance of this signal-mediated pathway is evident in that fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy secrete rather than target most of their lysosomal enzymes. Thus, the molecular theme of I-cell disease is that of faulty lysosomal targeting, the inability to transport (i.e., sort) lysosomal enzymes from their site of synthesis to the lysosome. 

Hurler s syndrome (252800) is caused by a deficiency of L-iduronidase, an enzyme normally expressed in most human cell types. It was demonstrated by Neufeld that exogenous L-iduronidase could be taken up by deficient cells via a targeting signal that directed the enzyme to its normal lysosomal location. Which of the therapeutic strategies below would be the most realistic and efficient mode of therapy ... 

From the Golgi apparatus, the proteins are transported by vesicles to various targets in the cells—e.g., to lysosomes (4), the plasma membrane (6), and secretory vesicles (5) that release their contents into the extracellular space by fusion with the plasma membrane (exocytosis see p. 228). Protein transport can either proceed continuously (constitutive), or it can be regulated by chemical signals. The decision regarding which pathway a protein... 

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