Lysosomes Flashcards
What is the key function of lysosomes?
The key function is to carry out digestive hydrolytic reactions
What are hydrolytic enzymes?
Hydrolytic enzymes are enzymes which catalyse reactions which break covalent by utilising water
Glycosidases hydrolysed carbohydrates
Nucleases break down nucleic acids
Phosphatases remove phosphate groups and sulfatases remove sulphate groups
Why are there heterogeneous contents inside lysosomes?
Inside lysosomes there are substrates at different stages of degradation therefore heterogenous contents
What organelle-specific membrane proteins in lysosomes?
Vacuolar ATPase (v-ATPAse)- very large protein complex which pumps protons into the lumen of the lysosome resulting in the right pH
Ion channel and transporters specific to the contents being released:
cholesterol transporter for cholesterol products
Sugar for the products of carbohydrate hydrolysis
Nucleoside transporter for broken down RNA and DNA
Amino acid for protein break down
Tethering factors involved in vesicle tethering
Small GTPases also involved with vesicles
SNAREs responsible for vesicle fusion
The motor adaptors allow the lysosomes to attach to the microtubules for transport
What are melanosomes and how are they produced?
Melanosomes are mostly produced by melanocytes
Mature melanosomes are characterised by high concentrations of melanin
Melanin can absorb UV light therefore important
Mature melanosomes are produced in a four step process starting with endosomes that require the specific proteins for producing melanin and making up the specific composition through a series of fusion and fission processes
While they are produced by melanocytes they are transferred to keratinocytes
What are the different ways substrates are delivered to lysosomes?
Extracellular substrates are taken up through endocytosis:
Fluid-phase endocytosis of soluble molecules and lipoproteins (includes receptor-mediated endocytosis)
Phagocytosis of particles >0.5 um
Intracellular substrates:
Microautophagy (invagination of the lysosomal membrane)
Macroautophagy (cytosol or organelles wrapped in ER membrane, which then fuses with lysosomes)
Selective transport of proteins across the lysosomal membrane
What is the function and structure of Low Density Lipoprotein (LDL)?
Very high concentrations in the plasma of humans are associated with a high risk of cardiovascular disease
The biological role of LDL is as a supplier of building blocks for cellular membranes
At the core you have neutral lipids; cholesteryl ester and triglycerides
Cholesteryl ester is a cholesterol molecule that is esterified with a fatty acid
They are surrounded by a lipid monolayer consisting of unesterified cholesterol and phospholipids
Associated with the monolayer shell, is a protein called apoprotein B-100 which is important for the recognition of these articles by cell-surface receptors
Recall the process through which LDL is taken up into the lysosome
The surface receptors are called LDL receptor molecules
When LDL particles bind to the LDL receptor this leads to the formation of a coated pit which captures the LDL molecules bound to the LDL receptors
the coated pits can pinch off through vesicular/inwards budding into the inside of the cell leading to the formation of early endosomes
As the pH drops in the vesicles, this triggers the dissociation between the LDL particle and the receptor and the LDL receptor molecules can then recycle back to the cell surface to be used again
The LDL molecules are then delivered to the late endosomes/lysosomes
Here the cholesteryl ester molecules as hydrolysed to form cholesterol and fatty acids from which they will then be released
Recall the steps of phagocytosis
initially the particle will bind to the cell surface and t is then engulfed
Typically this occurs through the plasma membrane wrapping itself around the particle
This structure that forms through this process of engulfment is called a phagosome
At this stage lysosomes will fuse with the phagosome to form a phagolysosome
The lysosomes deliver the hydrolytic enzymes, the ATPase pumps protons which leads to the acidification of the phagolysosome
The acidic pH activate the hydrolytic enzymes which can then digest the particle that’s been taken up
What happens to substrates delivered by macroautophagy?
What are the different types of macroautophagy?
Initially a structure is formed that produces a double membrane that can wrap around the intracellular particle e.g. organelles This forms an autophagosome This then fuses with the lysosome which forms an autophagolysosome and again the lysosomes deliver the hydrolytic enzymes and proton pumps which decrease the pH allowing the hydrolytic enzymes to break down the contents inside the autophagolysosome Mitophagy- mitochondria Pexophagy- peroxisomes Ribophagy-ribosomes Lipophagy- lipid droplets Chlorophagy- chloroplasts Xenophagy- infectious particles
What post-translational modification do lysosomal hydrolases go through in the ER?
Protein glycosylation
Lysosomal hydrolases are port-translationally modified by the protein N-glycosylation
As the protein, still being synthesised, enters the lumen of the ER, a large carbohydrate structure is transferred onto the protein specifically on an asparagine residue (whose one letter code is N hence N-glycocylation)
Pretty much all of these lysosomal hydrolases receive these oligosaccharides which are then subsequently modified in a series of steps
What is the mannose 6-phosphate (M6P) pathway and what happens?
This is the major route for targeting lysosomal enzymes to lysosomes
This mannose 6 phosphate residue is added in the cis Golgi to the protein
And once the protein reaches the trans Golgi the mannose 6-phosphate residue is recognised by a specific receptor called the M6P receptor
Here, the complex of receptor with its modified mannose 6-phosphate ligand, clusters in the membrane in a way that leads to the formation of budding vesicles using a specific protein called the clathrin coat
These clathrin coated vesicles then carry the M6P receptor and M6P modified lysosomal hydrolases towards late endosomes from where they can be transported onwards to lysosomes
What is I cell disease and what causes it?
A lysosomal storage disorder
An autosomal-recessive disorder caused by a deficiency of the enzyme UDP-N-acetylglucosamine
Here no mannose 6-phosphate tag is created
As a consequence, the lysosomal hydrolases behave as if they are secreted proteins since they cannot be recognised by the M6P receptor they will follow the fate of secreted proteins and therefore can be found in the bloodstream of such patients
What are the symptoms of I cell disease?
I cell disease (mucolipidosis type II) patients display:
Skeletal abnormalities
Developmental delay
Enlarged liver and spleen
Impaired hearing
Death from pneumonia or congestive heart failure usually occurs within the first decade of life
