Lysosomal protein degradation

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. 

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. 

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). 

In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62 [48], suggesting that similar in vivo mechanisms known to be present in s-IBM musde fibers might contribute to the p62 increase in them. 

L. Marzella, H. Glaumann, Autophagy, Microautophagy and Crinophagy as Mechanisms for Protein Degradation , in Lysosomes Their Role in Protein Breakdown , Eds. H. Glaumann, F. J. Ballard, Academic Press, London, 1987, p. 317-367. 

Ferhnz, K., linke, T, Bartelsen, O., WeUer, M., and Sandhoff, K., 1999, Stimulation of lysosomal sphingomyehn degradation by sphingohpid activator proteins. Chem Phys Lipids 102 35-43. 

The problem we have not yet touched upon is how components can specifically move from one cellular component to another. Both the entry and the exit of SFV spike proteins are dependent on a number of such cellular processes. The newly synthesized spike proteins move from the ER to the Golgi complex and then to the cell surface. The cell surface membrane is continuously retrieved by endocytosis into endosomes. From here the endocytosed membrane components probably recycle back to the cell surface, but some components may also be channeled into lysosomes for degradation. Especially in cells with secretory activity, the recycling pathway from the cell surface also includes the Golgi complex (see Farquhar and Palade, 1981). 

Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin Al, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 1991 266(26) 17707-17712. 

The first two are quantitatively the most important. Proteins that are taken up directly by the lysosomes have specific short amino acid sequences which are bound by a recognition protein that transports them to the lysosome. The concentration of the recognition protein increases in starvation and other conditions in which the concentrations of anabolic hormones are low. Thus, protein degradation is stimulated under these conditions. 

Some intracellular protein degradation (proteolysis) takes place in the lysosomes (see p. 234). In addition, there are protein complexes in the cytoplasm, known as pro-teasomes, in which incorrectly folded or old proteins are degraded. These molecules are recognized by a special marking (see p. 176). The proteasome also plays an important part in the presentation of antigens by immune cells (see p. 296). 

The functional proteins in the cell have to be protected in order to prevent premature degradation. Some of the intracellularly active proteolytic enzymes are therefore enclosed in lysosomes (see p. 234). The proteinases that act there are also known as cathepsins. Another carefully regulated system for protein degradation is located in the cytoplasm. This consists of large protein complexes (mass 2 10 Da), the proteasomes. Proteasomes contain a barrel-shaped core consisting of 28 subunits that has a sedimentation coef cient (see p. 200) of 20 S. Proteolytic activity (shown here by the scissors) is localized in the interior of the 20-S core and is therefore protected. The openings in the barrel are sealed by 19-S particles with a complex structure that control access to the core. 

The answer is D. As this patient ages, a variety of skeletal defects and short stature that are consistent with a lysosomal storage disease (mucolipidosis), either I-cell disease or pseudo-Hurler polydystrophy, are developing. Both diseases arise from a deficiency of an enzyme involved in synthesis of the Man-6-P marker on lysosomal enzymes. Such misaddressed proteins are secreted rather than trafficked to the lysosomes. The degradative function of lysosomes is impaired as a result and the organelles tend to accumulate waste products (hence, the term storage disease ). It is these inclusion bodies or dense structures that would be visible by microscopic examination of the patient s cells in a biopsy specimen. 

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