Lysosome and Lysosomal Storage Disease Flashcards
List the major characteristics of a lysosome that define it as an organelle and distinguishes it from early endosomes and other pre-lysosomal compartments
The lysosome contains digestive enzymes that actively degrade things in the cell. The early endosomes do not contain the digestive enzymes that are in an active form. Also the pH of the lysosome is much lower (around 5) and the lysosome has will contain LAMPs that prevent its degradation
Describe how lysosomes remodel and maintain extracellular components comprising the connective tissue matrix
The lysosomes will form multivesicular bodies that contain membrane proteins, especially those that are embedded in the membrane. This allows lysosomes to then for from these and degrade the membrane proteins that could play a role in comprising the connective tissue matrix.
Describe the role of lysosomes in maintaining the structural and functional integrity of cells.
The lysosomes are critical in degrading membrane proteins and other features of the cell such as dead organelles and bacteria. This maintains the structural and functional integrity of the cells because it keeps the cells from becoming overloaded with dead organelles, old proteins, and bacteria that can cause the proteins to aggregate or the bacteria to infect the cell.
Compare the signals for targeting enzymes to the ER and for targeting enzymes to the lysosome
The KDEL sequences keep the proteins localized to the ER and if they go to the Golgi by chance they are brought back to the ER via KDEL receptor proteins and COPI coats. The lysosomal enzymes contain a Mannose-6-phosphate that gives it a signal for the lysosome. It will be transferred to the Golgi, and in the golgi, the GlcNAc phosphtransferase will associate with a UDP-GlcNAc and the enzyme with a proteinaceous signal patch that binds to the GlcNAc Phosphotranferase enzyme. This will then add a phosphate and a GlcNAc to the protein. The GlcNAc will later dissociate. This M6P can then bind to M6P receptors in the trans golgi which target the protein to the lysosome with a clathrin coat.
Describe the functions of the endosomes in the transport of enzymes to lysosomes
When proteins have the M6P and are exported from the Golgi, they are first dropped off at a late endosome. The late endosome will allow the enzyme to mature due to its lower pH. This lower pH is first shown when the receptor allows the protein to dissociate because the pH is lower. Then the phosphate is removed to get a fully active lysosomal hydrolase. The M6P receptors are recycled back to the golgi
Predict the consequence of a mutation that results in a nonfunctional N-acetyl-glucosamine (GlcNAc) phosphotransferase
Now, the lysosomal hydrolases can no longer be transported to the lysosome because they will not be phosphorylated by the GlcNAc phosphotransferase and thus cannot bind to the M6P receptor that will take it to the lysosome. Thus these proteins will most likely remain in the normal exocytosis pathway and accumulate in the exterior of the cells and cause the lysosomes to not be active.
Describe the biological significance of this proteolytic process (proenzyme to active enzyme)
In the ER the enzyme is made as a proenzyme, meaning that it needs to be processed in some way to become active. This remains the case in the Golgi as well. This is important because the ER is making and the Golgi is transporting TONS of proteins. If the hydrolase was active, it would simply degrade these proteins too and have terrible effects on the cell. The protein becomes reversibly active in a low pH (in the endosome) and then a hydrolase will cleave it and it is now fully active.
Compare the proteolytic processing of lysosomal enzymes and secretory proteins with respect to where in the cell processing occurs and the enzymes likely to be responsible for the processing reactions.
The processing of the enzymes starts to take place in the endosome because it has a low pH which reversibly activates the enzyme. Then, in the lysosome, the enzyme is likely to become active via proteolytic cleavage by another hydrolase. This hydrolase is also like to be in the lysosome because of 2 reasons. The first is it needs to be active in the pH of about 5. The second is that you wouldn’t want the hydrolase to be active anywhere else!
Identify the source and kinds of cellular proteins degraded in lysosomes
One can use the analogy of a subcellular “stomach”. These degradative enzymes have to be enclosed within an organelle, to enclose an acidic site for macromolecular degradation. Note that these enzymes, as a group, can degrade virtually every biological macromolecule. The enzymes typically degrade macromolecules in an organized sequential fashion (i.e., from the “ends” of the polymers). The enzymes can even degrade organelles, such as old or damaged mitochondria.
It is also responsible for degrading membrane proteins or transmembrane proteins.
Identify the sources and kinds of non-proteinaceous constituents of cells that are degraded in cells
The lysosomes also degrade proteoglycans or proteins with sugars, sugars, lipids, etc. The lysosome literally has enzymes to practically degrade every substituent. For example, the lysosomes degrade dead organelles. These organelles contain every type of macromolecule and the lysosome can still degrade it! They also degrade mitochondria, bacteria, and many other things.
The substrates for lysosomal degradation come from many sources. Theoretically, the substrates could come into lysosomes through pores or by active transport, but that is not how they come in. They all get delivered from vesicles that fuse with the existing lysosome. For example, in the case of bacteria, they get phagocytosed (phagocytosis is different than endocytosis) and then the phagosome fuses with the lysosome, making it so that the bacteria are exposed to the degradative enzymes. In the case of substrates from the outside of the cell, receptor mediated endocytosis brings the molecules into endosomes, which mature by fusion into lysosomes. In the case of dying or damaged organelles, a cell membrane (probably derived from the ER) thins out and then surrounds the organelle, making a double membrane around the organelle. This is called “autophagy” and the resulting organelle is an autophagosome. Next, the autophagosome fuses with the lysosome and the enzymes eat away at the inner membrane and then the organelle. Autophagy is a process you will want to remember.
Endocytosis
Might come in through receptor mediated endocytosis where receptors bind ligands like food, transferred to an early endosome, then late endosome which matures into a lysosome
Phagocytosis
Bacteria can invade a cell and be digested by being surrounded by a membrane
Autophagy
Mitochondria degradation. The mitochondria gets membranes around it which fuses with a lysosome
Describe how substrates are delivered to lysosomes
The three main methods are via Endocytosis, phagocytosis, and autophagy.
1) Endocytosis involves the cell intaking substrate from the outside of the cell. These substrates could, for example, bind to a receptor that will then form a clathrin coat and transport the vesicle to the lysosome. A subcategory of the endocytosis is the degradation of membrane bound proteins. This is down by monoubiquitination of the tail of the receptor protein which then tags it for degradation. It will endocytose but form a multivesicular body in order to be degraded completely because otherwise the whole thing would not be degraded
2) Phagocytosis involves the cell engulfing large particles such as bacteria. It encapsulates the bacteria and forms a phagosome that can then be transported to the lysosome for degradation
3) In autophagy, the cell is encapsulating its own organelles, like a dead mitochondria for example. This is done by forming a lipid membrane around the mitochondria from lipids that bud from the ER since it is where lipids are made. It then forms an autophagosome that can be transported to the lysosome for degradation.
Distinguish between phagocytosis and endocytosis
Phagocytosis is a type of endocytosis but it involves a large solid particle like a bacterium and usually does not require the binding of membrane-bound receptors.
