Protein lysosomes

Mammals, fungi, and higher plants produce a family of proteolytic enzymes known as aspartic proteases. These enzymes are active at acidic (or sometimes neutral) pH, and each possesses two aspartic acid residues at the active site. Aspartic proteases carry out a variety of functions (Table 16.3), including digestion pepsin and ehymosin), lysosomal protein degradation eathepsin D and E), and regulation of blood pressure renin is an aspartic protease involved in the production of an otensin, a hormone that stimulates smooth muscle contraction and reduces excretion of salts and fluid). The aspartic proteases display a variety of substrate specificities, but normally they are most active in the cleavage of peptide bonds between two hydrophobic amino acid residues. The preferred substrates of pepsin, for example, contain aromatic residues on both sides of the peptide bond to be cleaved. 

Disorders caused by mislocalization of lysosomal proteins (e.g., mutations in the N-acetylglucosamine 1-phosphotransferase leading to inclusion cell disease). 

Journet A et al. Towards a human repertoire of monocytic lysosomal proteins. Electrophoresis 2000 21 3411-3419. Soskic V et al. Functional proteomics analysis of signal transduction pathways of the platelet-derived growth factor beta receptor. Biochemistry 1999 38 1757-1764. Thiede B et al. A two dimensional electrophoresis database of a human Jurkat T-cell line. Electrophoresis 2000 21 2713-2720. 

Lysosomal proteins are also sorted and targeted in the trans-Golgi network 150... 

Von Figura, K. Molecular recognition and targeting of lysosomal proteins. 3 642-646,1991. 

Defect in lysosomal enzyme protection Defects in soluble non-enzymatic lysosomal proteins... 

Nauseef, W. M. (1987). Posttranslational processing of a human myeloid lysosomal protein, myeloperoxidase. Blood 70,1143-50. 

Hofmann, K. and Falquet, L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem Sci 2001, 26, 347-50. 

Gaucher disease, and Krabbe disease. LSDs are classified as mucopolysaccharidoses (MPS), lipidoses, or mucolipidoses depending on the nature of the stored material. Over 40 LSDs are known and they have a collective incidence of approximately 1 in 7000-8000 live births (Meikle et al., 1999 Poorthuis et al., 1999 Winchester et al., 2000). Most of the genes for these lysosomal proteins have been cloned, permitting mutation analysis in individual cases. 

Fig. 10.1. Lysosomal enzymes are synthesized as precursor proteins that undergo extensive modifications during transport to the lysosome. Newly synthesized lysosomal proteins have an amino-terminal signal sequence that mediates... 

Lysosomal proteins are targeted to the lysosomes via the addition of a mannose 6-phosphate signal that is added in the ds-compartment of the Golgi and is recognized by a receptor protein in the frans-compartment of the Golgi. The protein is then transported by specialized vesicles to a late endosome that later matures into a lysosome. The mannose 6-phosphate receptor recycles back to the Golgi for re-use. 

Not all lysosomal proteins take the normal route of protein targeting some end up being exported by the cell and must be retrieved. This scavenger pathway works as follows. The lysosomal glycoprotein binds to mannose 6-phosphate receptors in the plasma membrane and is internalized again by endocytosis (Fig. 5). This process, called receptor-mediated endocytosis, creates an endocytic vesicle (or endosome) that then delivers the lysosomal protein to the lysosome by fusion (see Topic E4). 

Prenatal diagnosis of I-cell disease has been based on greatly reduced phosphotransferase activity (cf. Biochemical Perspectives section) and abnormal intracellular-extracellular distribution of lysosomal enzymes in cultured amni-otic fluid cells (Table 17-3).As indicated in Table 17-3, amniotic fluid cells secrete large amounts of lysosomal enzymes into the extracellular medium. Decreased levels of lysosomal enzymes in chorionic villi obtained by biopsy have also been observed in I-cell disease however, the characteristic secondary effect (i.e.,increased levels of lysosomal enzymes in the extracellular compartment) is only partially expressed or not expressed at all in chorionic villi, suggesting an alternative mechanism for the transport of lysosomal proteins. Although... 

Does defective lysosomal catabolism in I-cell disease somehow feed back to affect the expression of lysosomal proteins and their receptors Compared with control fibroblasts, twofold increases in man-6-P/IGF-II receptors have been observed for fibroblasts from patients with I-cell disease. This increase in receptor concentration stems from an increased rate of synthesis, not from differences of receptor stability. Interestingly, when they are exposed to insulinlike growth factors I and II or tumor-promoting phorbol esters, I-cell fibroblasts respond differently from control fibroblasts. These observations indicate multiple regulatory sites in the man-6-P/IGF-II receptor pathway. 

E4. Eldred, G. E., Lipofuscin fluorophore inhibits lysosomal protein degradation and may cause early stages of macular degeneration. Gerontology 41 Suppl. 2, 15—28 (1995). 

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