LYSOSOME_review
3 Pages

LYSOSOME_review

Course Number: BICD 110, Winter 2008

College/University: CSU Northridge

Word Count: 867

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Lysosome A. Characteristics - Digestive organelles of animal cells - Heterogeneous population of lysosomes within a single cell - Mixture of small and large lysosomes - Bags of Hydrolytic Enzymes - Enzymes = Acid Hydrolases - Function at low pH [~pH = 5] - Low pH is maintained by a H+ Pump - Degrades proteins, lipids and other cellular constituents taken in by endocytosis, phagocytosis, etc. B. Three Pathways to...

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A. Lysosome Characteristics - Digestive organelles of animal cells - Heterogeneous population of lysosomes within a single cell - Mixture of small and large lysosomes - Bags of Hydrolytic Enzymes - Enzymes = Acid Hydrolases - Function at low pH [~pH = 5] - Low pH is maintained by a H+ Pump - Degrades proteins, lipids and other cellular constituents taken in by endocytosis, phagocytosis, etc. B. Three Pathways to Degradation in Lysosomes 1. Autophagy - Destruction of obsolete parts of the cell itself (i.e various organelles) 2. Phagocytosis - Destruction of large particles and microorganisms 3. Endocytosis - Destruction of macromolecules taken up from extracellular fluid C. Lysosomal Hydrolases 1. Lysosomal Proteins - Lysosomal hydrolases are transported via the secretory pathway and are diverted to the lysosome. - *Note: - Lysosomal Hydrolases are soluble proteins, NOT lysosomal membrane proteins - Lysosomal membrane proteins would possess a different signal than soluble lysosomal proteins. 2. Lysosomal Hydrolase Signal - Mannose-6-Phosphate (M6P) - The presence of M6P on the lysosomal hydrolase targets the lysosomal hydrolase to the lysosome 3. Mannose 6-Phosphate Addition to Lysosomal Hydrolases in cis Golgi - Lysosomal hydrolases possess a "signal patch" that is recognized by the enzyme N-Acetylglucosamine (GlcNAc) phosphotransferase in the cis Golgi - GlcNAc phosphotransferase aligns lysosomal hydrolase within the catalytic site - Phosphate is added within the catalytic site of the GlcNAc phosphotransferase - Result = Lysosomal hydrolase with M6P attached 4. Recognition of Lysosomal Hydrolase with Mannose 6-Phosphate in trans Golgi - Mannose 6-Phosphate is recognized by specific Mannose 6-Phosphate Receptors in the trans Golgi 5. Transport from the trans Golgi to the Lysosome - Lysosomal hydrolases with M6P bind to a M6P receptor in the trans Golgi - In the trans Golgi, the lysosmal hydrolase-M6P bound to the M6P receptor are packaged into a clathrin coated vesicle - Mobilized initially to the late endosome : - In the late endosome: - The lysosomal hydrolases dissociate from the M6P receptor due to the acidic pH of the late endosome - The phosphate on the M6P signal attached to the hydrolase is removed from the mature hydrolase - CRITICAL - If phosphate was NOT removed, then the lysosomal hydrolase would be recycled back to the trans Golgi (i.e would not be directed to the lysosome) - M6P receptor is recycled back to the trans Golgi - Eventually, the late endosome matures into a lysosome - Lysosomes are thought to be produced by a gradual maturation process, during which endosomal membrane proteins are selectively retrieved from the developing lysosome by transport vesicles that deliver these proteins back to endosomes the or trans Golgi network - Mature lysosomes form from the late endosomes, accompanied by a further decrease in internal pH. 6. Summary- Key Points: - The lysosomal hydrolases contain N-linked oligosaccharides that are covalently modified in a unique way in the cis Golgi network so that their mannose residues are phosphorylated (M6P) - These mannose 6-phosphate (M6P) groups are recognized by an M6P receptor protein in the trans Golgi network that segregates the hydrolases and helps package them into budding transport vesicles (clathrin- coated vesicles) that deliver their contents to late endosomes - The M6P receptors shuttle back and forth between the trans Golgi network and these endosomes. - The low pH in the late endosome dissociates the lysosomal hydrolases from these receptors, making the transport of the hydrolases unidirectional - The late endosome eventually matures into a lysosome. D. FYI - Lysosomal Diseases 1. I- Cell Disease (I = Inclusion) - In this disease almost all of the hydrolytic enzymes are missing from the lysosomes of fibroblasts, and their undigested substrates accumulate in lysosomes, which consequently form large "inclusions" in the patients' cells. - In I-cell disease patients, all the hydrolases missing from lysosomes are found in the blood. - Hydrolases fail to be sorted properly in the Golgi apparatus - Thus, the hydrolases are secreted rather than transported to lysosomes. - The missorting has been traced to a defective or missing GlcNAc-phosphotransferase - GlcNAc-phosphotransferase is responsible for attaching the M6P signal in the cis Golgi - Since lysosomal enzymes are not phosphorylated in the cis Golgi network, they are not segregated by M6P receptors into the appropriate transport vesicles in the trans Golgi network - Instead, they are carried to the cell surface and secreted by a default pathway. - Secreted into the blood 2. Tay- Sachs 3. Asbestosis/ Silicosis - Inhalation of asbestosis or silica: - Lysosomes are unable to breakdown asbestosis or silica - Asbestosis or Silica accumulates within lysosomes - Lysosomes start leaking - Leads to lung damage II. Early Endosomes/ Late Endosomes A. Functional Definitions 1. Early Endosome - Endosome just beneath the plasma membrane - Takes about 1 minute for an external tracer to reach the early endosome 2. Late Endosome - Endosome found closer to the Golgi/ Nucleus - Takes about 5- 15 minutes for an external tracer to reach the late endosome - More acidic than early endosomes - pre- Lysosomes B. Are Early/Late Endosomes Distinguishable? - Yes, they are distinguishable, BUT sometimes in transition C. Transition Pattern between Early Endosome/ Late Endosome/ Lysosome - Transition state between Early Endosome to Late Endosome - Multivesicular body
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