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z:Cell 300 > Lecture 10: Lysosome Biogenesis > Flashcards

Lecture 10: Lysosome Biogenesis Flashcards

1
Q

Lysosomes are _____

A

heterogenous group of membranous organelles containing > 50 types of acid hydrolases (enzymes) that degrade macromolecules

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2
Q

lysosomes are involved in recycling so ___

A

breakdown products can be transported to cytosol for reuse

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3
Q

lysosomal enzymes have pH optimum of _____ compared to the cytoplasm’s ___

A
  • 5
  • 7.2
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4
Q

pH of lysosome is maintained by ____

A

proton pump (membrane protein complex with ATPase activity)

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5
Q

pH of lysosomes keeps its enzymes from ___

A

being active in the cytosol and digesting the cell

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6
Q

size of lysosomes ____

A

varies in zie (10-fold)

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7
Q

the size of lysosomes reflects ____

A

variety of digestive functions of intracellular and extracellular debris

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8
Q

lysosomes contain ____ which form dense precipitate in the presence of lead

A

-acid phosphatase

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9
Q

lysosomal storage disorders are ____

A

group of genetic disease in which people have reduced levels of lysosomal enzymes
(more enzymes missing, the worse the disease)

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10
Q

lysosomal storage disorders life expectancy

A

<15 years

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11
Q

lysosomal storage disorders inheritance pattern

A

autosomal recessive

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12
Q

lysosomal storage disorders result

A

lysosome cannot perform its recycling function and becomes clogged with proteins, lipids, and carbohydrates than can not be degraded

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13
Q

lysosomal storage disorders (Tay Sachs)

A

-lack of hexosaminidase (hydrolyzes GM2)
-progressive neurodegeneration

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14
Q

lysosomes + heart health

A

-you can get buildup of LDL that block major arteries (heart attack/coronary heart disease)
-cell have LDL receptors that bring cholesterol into cell to be degraded by lysosome

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15
Q

lysosomes + covid 19

A

-virus deacidify lysosomes to exit cell via lysosomal trafficking

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16
Q

3 major pathways for entry into lysosomes for degradation of intracellular + extracellular material

A

1) endocytosis
2) phagocytosis
3)autophagy

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17
Q

endocytosis (def.)

A

-receptor mediated uptake of proteins and lipids at cell surface
-endocytosed material is delivered to lysosomes via endosomal system

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18
Q

phagocytosis (def.)

A

engulfment of large particles(bacteria + debris) at cell surface + delivery to lysosomes directly

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19
Q

autophagy (def.)

A

ER-derived membrane wrap round organelles to form autophagosomes

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20
Q

phagocytosis + autophagy have this in common

A

-don’t used endosomes as transport intermediate

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21
Q

endosomes (def.)

A

membranous organelles with acidic lumens that receive and sort cargo from TGN + endocytic cargo from PM

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22
Q

early endosomes (ee) are found _____ and receive cargo from ____

A

-near PM
-PM primarily

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23
Q

late endosomes (LE)/ multi-vesicular bodies are found ___ and receive cargo from ___

A

-near nucleus/golgi
-early endosomes +TGN, contain internal vesicles

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24
Q

newly-synthesized lysosomal proteins have multiple ____

A

pathways for delivery into lysosomes

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25
Q

many but not all lysosomal enzymes (soluble) are modified by ____

A

addition of M6P

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26
Q

____ contain membrane proteins

A

lysosomes

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27
Q

Glycoproteins destined for lysosomes are ____ in ER and contain the same ______ as non-lysosomal glycoproteins

A

-N-glycosylated
-core oligosaccharides

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28
Q

generation of M6P-lysomal protein in Golgi

A

1)N-acetylglucosamine (GlcNAc) phosphotransferase (Enzyme 1)- transfers GlcNac reside to mannose residue on lysosomal protein (phosphate bond) (with Uridine dpn GlcNAc —> UMP)
2)phosphodiesterase (enzyme 2) removes GlcNac leaves M6P on lysosomal protein

29
Q

___ distinguishes between lysosomal enzymes & regulatory secretory proteins in Golgi by recognizing lysosomal hydrolases

A

N-acetylglucosamine (GlcNAc) phosphotransferase

30
Q

in vitro findings: endo H treated lysosomal enzymes ______ to intact lysosomal enzymes

A

inhibit phosphorylation

31
Q

in vitro findings: fragments of endo H treated lysosomal enzymes ______ to intact lysosomal enzymes

A

do not inhibit phosphorylation

32
Q

in vitro findings: denatured lysosomal enzymes ______

A

are not phosphorylated properly

33
Q

in vitro findings:
N-acetylglucosamine (GlcNAc) phosphotransferase
bind only to______

A

fully folded lysosomal enzymes

34
Q

Lysosomal recognition determinant is _____

A

conformation/folding-dependent as opposed to linear sequence like KDEL motifs

35
Q

cathepsin D is a ___

A

lysosomal hydrolyase

36
Q

pepsinogen has no ___

A

natural glycosylation sites

37
Q

only high mannose type glycans become ____

A

phosphorylated by Enzyme 1

38
Q

Addition of M6P prevents further ____

A

processing of N-linked glycans to endo H resistant types

39
Q

resistance to endo H means what about modification by M6P?

A

-evidence that N-linked glycans are not modified by M6P

40
Q

secreted proteins are all ___

A

100% resistant to endo H

41
Q

if its going to lysosomes, then it can’t be ___

A

secreted

42
Q

M6P receptor column

A

-CD would bind (Run thru portion would contain Pep)
-rinse with M6P (Bound fraction would contain CD0
-chimeric proteins with M6P would also bind (CP2)

43
Q

M6P receptor column: CP2 -chimeric

A

shows us that the major lysosomal determinant is in C-terminus of CD

44
Q

CD C-terminus has two ___

A

discontinuous regions that are required for the generation of M6P (region A and B)

45
Q

cathepsin D (regions A & B) are rich in ___

A

lysine (this is absent in Pep)

46
Q

lysines alone are not ___

A

lysosomal recognition component

47
Q

what is total lysosomal recognition component of CD?

A

lysine 203 in region A and lysines (265-348) in region B(all of region B)

48
Q

Enzyme 2 recognized folded region_____ + one lysine from region ____

A

-B
-A

49
Q

If you disrupt folded structure of lysosomal protein, ___

A

it won’t bind to enzyme 1

50
Q

GlcNAc phosphotransferase (Enzyme 1) recognizes a signal patch on lysosomal enzymes–involves lysine residue and _____

A

-Catalyzes transfer of GlcNAc phosphate (from UDP-N-acetylglucosamine donor) to mannose in 6’ position of N-linked oligosaccharide

51
Q

GlcNAc phosphotransferase works where?

A

in cis-Golgi

52
Q
  1. Phosphodiesterase (enzyme 2) removes _____
A

GlcNAc leaving mannose 6-P

53
Q

Mannose 6-P is recognized by ____in ____

A

-mannose 6-P receptors (MPR)
-TGN

54
Q

mannose 6-P receptors (MPR)

A

Transmembrane proteins that cycle between TGN,
endosomes and plasma membrane

55
Q

two types of mannose 6-P receptors (MPR)

A

CD-MPR (cation-dependent)
CI-MPR (cation-independent) - LARGER
-both essential to transport to lysosomes

56
Q

MPR directs incorporation into

A

clathrin coated vesicles (CCVs)

57
Q

MPR binding site on ___

A

luminal sides of proteins

58
Q

ligands of MPR dissociate in ____ due to ___

A

-endosomes due to low pH

59
Q

MPRs contain multiple sorting signals in their cytoplasmic domains that _____

A

bind different adaptor/linker proteins

60
Q

Both receptors (MPR) are required for delivery of all lysosomal enzymes: (2)

A
  • Neither has exclusive affinity for specific lysosomal enzymes
  • Receptors have similar and overlapping functions
61
Q

type of targeting signal for lysosomal enzymes

A

Carbohydrate-dependent sorting i.e. M6P
Carbohydrate independent

62
Q

Carbohydrate independent targeting signal discovered through I-Cell Disease (lysosomal storage disease)

A

Cells lack GlcNAc phosphotransferase (enzyme 1)
* Complete lack of lysosomal enzymes in most cell types
– Lysosomal enzymes are secreted instead
-However, MPRs function normally and can take up lysosomal enzymes with M6P via endocytic pathway
-Cell type-specific: hepatocytes and lymphocytes have regular amount of enzymes

63
Q

Carbohydrate independent receptors (soluble lysosomal proteins)

A

Sortilin and LIMP-2 (they don’t bind to M6P)

64
Q

Targeting of Lysosomal Membrane proteins is _____ process

A

carbohydrate-independent

65
Q

Targeting of Lysosomal Membrane proteins: Sorting signals located in____ + type of signals

A

cytoplasmic domains
* Tyrosine-based motifs (YXXø)
* DiLeucine-based motifs»>LL + variations (IL)

66
Q

Targeting of Lysosomal Membrane proteins with what adaptors?:
protein interacts with _____ (TGN/endosomes) or ____ (plasma membrane) followed by clathrin coat.

A

-GGAs/AP-1 (TGN/endosomes)
-AP-2 (plasma membrane)

67
Q

Targeting of Lysosomal Membrane proteins: sorting can be direct from TGN (biosynethitc pathway): _______
or indirect via PM (endocytic pathway): _____

A

-TGN»>Late Endosomes»>Lysosomes
-TGN»>plasma membrane»>early endosomes»>late endosomes»>lysosomes

68
Q

Late endosomes fuse with ______ or _____

A

-preexisting lysosomes or preexisting endolysosomes

69
Q

Endolysosomes eventually mature into lysosomes as ______

A

hydrolases complete the digestion of their contents, which can include intralumenal vesicles.

z:Cell 300 (17 decks)

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