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MCBG > 9.1.16 Lecture > Flashcards

9.1.16 Lecture Flashcards

1
Q

What are lysosomes?

A

Acidic organelles found in every eukaryotic cell that contain hydrolytic enzymes and mediate intracellular digestion.

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2
Q

Typically, lysosomal hydrolytic enzymes degraded macromolecules in a ___ fashion.

A

Sequential

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3
Q

What keeps the pH low in lysosomes?

A

Proton ATPases

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4
Q

If a lysosome were to burst, what would happen?

A

The released enzymes would alarm the cell but would not be lethal, since the optimal pH for enzymatic action is less than 7, which is the pH of the cell.

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5
Q

Acid hydrolases work optimally at a pH of ___.

A

5

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6
Q

What are the 7 main acid hydrolases?

A
  1. Nucleases
  2. Proteases
  3. Glycosidases
  4. Lipases
  5. Phosphatases
  6. Sulfatases
  7. Phospholipases
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7
Q

___ evolve into lysosomes as they move to the cell interior and acquire ___.

A

Endosomes; hydrolytic enzymes

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8
Q

___ are the end of the endocytic pathway.

A

Lysosomes

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9
Q

Describe the endocytic pathway.

A

Plasma membrane > early endosome > late endosome > endolysosome > lysosome (note that cargo can enter the early endosome from the TGN as well)

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10
Q

As the endocytic pathway proceeds, the pH ___.

A

Decreases

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11
Q

Where do the enzymes needed for degradation in the lysosomes come from? Where do the substrates targeted for degradation in the lysosome come from?

A

Fed to lysosomes from the TGN; Early endocytic pathways

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12
Q

What happens to hydrolytic enzymes in the cis-golgi?

A

Fully folded but inactive glycoproteins from the ER get phsophorylated on mannose residues, destining them for the lysosome.

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13
Q

What happens to hydrolytic enzymes in the trans-golgi?

A

Phospho-mannose marked proteins get sorted for vesicular transport to endosomes and then to lysosomes.

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14
Q

Where do the substrates for lysosomal degradation come from?

A

Many sources, both extracellular and cytoplasmic

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15
Q

What are the three general ways substrates are transported to the lysosome?

A
  1. Bacteria from the extracellular space get phagocytosed (form phagosome)
  2. Substrates from outside the cell are brought in via receptor mediated endocytosis (form endosome)
  3. Dying/damaged organelles from inside the cell are enclosed by a double cell membrane from the ER via autophagy (form autophagosome)
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16
Q

True or false - lysosomes are defined by their appearance.

A

False - lysosomes are defined by a common set of properties.

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17
Q

What are the common set of properties that define a lysosome?

A
  1. Luminal pH of ~4.5
  2. Presence of active forms of lysosomal hydrolases
  3. Presence of lysosomal membrane proteins (LAMPs)
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18
Q

What do LAMPs do?

A

Form an inner lining to protect the lysosomes from enzymes

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19
Q

Lysosomal enzymes are phosphorylated on ___ residues in the ___.

A

Mannose; CGN

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20
Q

Virtually all proteins from the ER have ___ glycans.

A

N-linked

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21
Q

How are lysosomal enzymes phosphorylated on their mannose residues?

A

Signal patch on the lysosomal hydrolase (in its inactive zymogen form) and UDP-GlcNac bind to the enzyme GlcNac phosphotransferase. This allows for transfer of GlcNac-P to the 6-OH on mannose (release of UMP). Another enzyme removes GlcNac, leaving mannose-6-phosphate.

22
Q

The transport of enzymes to the lysosomes involves ___ receptors.

A

Mannose-6-phosphate

23
Q

Proteins marked with M-6-P move to the ___, where they bind to receptors.

A

TGN

24
Q

M6P receptors in the TGN are ___ proteins with cytoplasmic tails that interact with ___. Clathrin mediated budding from here makes transport vesicles that bind to ___. Here, the cargo is released and ___ removed by acid phosphatases. What happens to the empty receptors?

A

Transmembrance; clathrin adaptors; endosomes; 6-P; they are incorporated into retromer vesicles that bud from the endosomes and return to TGN.

25
Q

The one-way flow of proteins to the lysosome is caused by what?

A

Slowly decreasing pH levels in various organelles; note that this ultimately comes from the H+ ATPases.

26
Q

Once in the lysosome, digestive enzymes are activated by ___.

A

Proteolytic cleavage

27
Q

Lysosomal proteases are synthesized as ___. These proteases acquire limited proteolytic activity at a ___ pH. Once activated, the protease can do what?

A

Inactivate precursors; proenzymes; low; process additional inactive precursors

28
Q

Lysosomal enzymes that are accidentally secreted are recovered by ___. How does this work?

A

Receptor-mediated endocytosis; Plasma-membrane M6P receptors bind the escaped lysosomal enzyme. This is then returned to the lysosome by clathrin and receptor-mediated endocytosis.

29
Q

Lysosomes degrade plasma membrane proteins via ___.

A

Multivesicular bodies

30
Q

Describe the process of lysosomal degradation of plasma membrane proteins via multivesicular bodies.

A

The proteins receive a mark on the cytoplasmic tails (often ubiquitination conjugation). This mark places the proteins into a complex of proteins called ESCRT which stimulate an inward pinching off of a membrane vesicle.

31
Q

What is internal membrane fission?

A

Fission of a vesicle into a region that is the topological equivalent of the outside of the cell.

32
Q

Integral membrane proteins can be sorted into vesicles on the basis of what 3 things?

A
  1. Phosphorylation
  2. Intrinsic signals
  3. Monoubiquitination
33
Q

How can cell signaling be terminated?

A

By degrading receptors in lysosomes

34
Q

Many endocytosed proteins will avoid lysosomal degradation in what two ways?

A
  1. Endocytic vesicles can be recycled back to the plasma membrane.
  2. Endosomes bud and travel to the other side of a polarized cell via transcytosis
35
Q

Give an example of transcytosis.

A

Babies get protective maternal antibodies in this way. Maternal IgA binds to a baby’s Fc receptors. This transcytoses across intestinal epithelia and populate the internal fluids of the baby.

36
Q

Proteins are marked for ___ sorting from the ___.

A

Polarized; TGN

37
Q

Transmembrane proteins can sort at the TGN into or out of ___ before being selectively incorporated into vesicles.

A

Lipid raft microdomains

38
Q

Raft vesicles often sort to ___ cell surfaces while non-rafts often sort to ___ cell surfaces.

A

Apical (faces inward to lumen); Basolateral (faces outward away from lumen)

39
Q

Cells can encapsulate cytoplasmic constituents and organelles in ___ vacuoles for eventual degradation.

A

Autophagic

40
Q

Autophagosome formation requires a ___ and ___.

A

Donor organelle (usually the ER); nucleating signals

41
Q

Cells can also bring in dead material via ___, in which the dead cell is surrounded by a lipid bilayer at completion.

A

Phagocytosis

42
Q

Some macromolecules brought to the lysosome are hard to digest. Why?

A

Extracellular matrix proteins, cell surface proteins, and membrane lipids internalize via endocytosis and phagocytosis. These include membrane glycosphingolipids, glycoproteins, and proteoglycans in both the carbohydrate-rich glycocalyx on the surface of cells and in the surrounding connective tissue matrix.

43
Q

___ maintain and remodel connective tissue. This involves synthesis of matrix constituents and their degradation within lysosomes. This process must be maintained in a ___.

A

Fibroblasts; steady state

44
Q

N-linked glycoproteins found in biological membranes and the extracellular matrix contain 1+ branched, complex oligosaccharide chains. Their degradation requires cooperation of several ___.

A

Lysosomal glycosidases

45
Q

What are lysosomal storage diseases?

A

Genetic conditions due to lysosomal enzyme deficiencies with the corresponding accumulation of substrates within lysosomes.

46
Q

What is the incidence of lysosomal storage disease?

A

1/6,000

47
Q

What is the inheritance pattern of lysosomal storage diseases?

A

Autosomal recessive (except Hunter syndrome and Fabry disease, which are X-linked recessive)

48
Q

The onset of clinical symptoms of lysosomal storage diseases usually occurs ___ in life.

A

Early; note that variants exist with onsets in adulthood.

49
Q

True or false - lysosomal storage diseases affect all tissues equally.

A

False - this depends in part on the tissue distribution of the relevant substrate

50
Q

How are lysosomal storage disease classified?

A

Based on the identity of the stored substrate

51
Q

What are several examples of lysosomal storage diseases?

A 
Mucolipidosis II (I-Cell Disease)
Fabry Disease
Metachromatic Leukodystrophy (MLD)
Hurler Disease
Gaucher Disease
Tay Sachs
52
Q

What are the two possible treatments for lysosomal storage diseases?

A
  1. Substrate reduction (not used, too many side effects)

2. Enzyme replacement therapy

MCBG (28 decks)

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