Lysosomes and Lysosomal Storage Diseases Flashcards
What are lysosomes?
Acidic organelles containing hydrolytic enzymes that mediate intracellular digestion
“Subcellular stomach”
How is the pH maintained within lysosomes?
proton-ATPases create a proton gradient across the lysosomal membrane
pH in lysosome ~5
How are lysosomes formed?
The endocytic pathway forms lysosomes
Endocytosis produces and endosome, which can acquire hydrolytic enzymes and become a lysosome
The pH becomes increasingly lower throughout the endocytic pathway
Where do hydrolytic enzymes originate?
They feed into lysosomes from the Golgi apparatus (cis and trans golgi network)
lysosomal enzymes are tagged with a mannose-6-phosphate
Do lysosomes digest intracellular or extracellar proteins?
BOTH
Extracellular proteins are digested by fusing lysosomes with phagosomes
Intracellular proteins can be digested by inducing autophagy
What features define a lysosome?
A luminal pH around 4.5
The presence of lysosomal hydrolases and a unique set of lysosomal membrane proteins (LAMPs)
How are lysosomal proteins distinguished from other proteins containing N-linked glycans?
A signal patch (formed by 3D folding) binds to a GlcNAc phosphotransferase which phosforylates the 6th carbon OH group of mannose to form M6P
True or false: Phosphorylation of 6-OH of mannose activates lysosomal hydrolases.
False
Lysosomal hydrolases are not active until they are in the lysosome in a low pH environment
Describe how proteins marked with M6P get from the Golgi apparatus to the endosome.
The TGN has M6P receptors with cytoplasmic tails that interact with clathrin adaptors, clathrin proteins.
M6P binds to receptors at pH ~ 6
Clathrin coated vesicles move the M6P cargo to endosomes
M6P released from receptors at pH < 6
M6P receptors are recycled back to the TGN
How does the cell deal with renegade enzymes marked with M6P?
Receptor mediated endocytosis allows for the lysosomal enzyme to be captured and returned back to the lysosome by clathrin coated vesicles
Relatively harmless because enzymes not active in pH of extracellular space
What are multivesicular bodies?
“vesicles within vesicles”
Used to degrade plasma membrane proteins that are tagged with ubiquitin
Protein complex ESCRT stimulates inward pinching off of a membrane vesicle to produce MVBs
Are endocytosed proteins always degraded in lysosomes?
No
Endocytic vessels can avoid lysosomal degradation by:
1) recycling back to original plasma membrane
2) transcytosing (travel to other membrane)
Describe the formation of an autophagosome
Cell encapsulate cytoplasmic constituents and organelles in autophagic vacuoles for eventual degradation
A donor organelle (probably ER) is required to form the double membrane around the targeted organelles
What is phagocytosis?
A way for cells to bring in large dead material for degradation
What is the glycocalyx?
The carbohydrate-rich layer on the surace of cell membranes
Contains glycoproteins and proteoglycans
