BCHM - Functions and Dysfunctions of Protein Processing Flashcards

1
Q

In the cytoplasmic pathway of protein sorting, where are the proteins destined for?

A

Cytosol, mitochondria, nucleus, and peroxisome

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2
Q

In the cytoplasmic pathway of protein sorting, where does protein synthesis begin and end?

A

Begins and ends on the free ribosomes of the cytoplasm

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3
Q

In the secretory pathway of protein sorting, where are the proteins destined for?

A

Endoplasmic Reticulum, lysosomes, plasma membrane, or secretion

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4
Q

In the secretory pathway of protein sorting, where does translation begin and end?

A

Begins on free ribosomes, but ends in ribosomes sent to the ER

Proteins undergo second part of synthesis in the ER

Have ER targeting signal sequences on first 20 amino acids (N-terminus)

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5
Q

In the cytoplasmic pathway, what signal moves the protein to the cytoplasm?

A

No signal required

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6
Q

In the cytoplasmic pathway, what signal moves proteins into the mitochondria?

A

N-terminal hydrophobic alpha-helix

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6
Q

In the cytoplasmic pathway, what signal moves proteins into the mitochondria?

A

N-terminal hydrophobic alpha-helix

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7
Q

In the cytoplasmic pathway, what signal moves the protein into the nucleus?

A

Lysine and Arganine rich signals

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8
Q

In the cytoplasmic pathway, what signal moves the protein into the peroxisome?

A

Serine, Lysine, Leucine signaling complex

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9
Q

In the secretory pathway, what moves the protein into the ER?

A

KDEL

Lysine, aspartic acid, glutamic acid, and leucine

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10
Q

In the secretory pathway, what moves the protein into the cell membrane?

A

N-terminal apolar signals

Examples include GLUT transporters

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11
Q

In the secretory pathway, what moves the protein into the lysosome?

A

Mannose-6-phosphate

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12
Q

In the secretory pathway, what moves the protein into a secretory vesicle for secretion?

A

Trp-rich domains

Tryptophan

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13
Q

During the import of mitochondrial proteins, HSP70 does what?

A

HSP70 is a chaperone protein that protects the mitochondrial protein from degradation

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14
Q

Describe the pathway of mitochondrial protein import

A

Proteins pass through TOM and then TIM. After that, they enter the matrix, and a peptidase cleaves the signaling sequence, trapping the protein within the mitochondrial matrix

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15
Q

Describe the pathway of nuclear protein import

A
  • Proteins pass through nuclear pores
  • Small proteins can pass through un-aided, but larger proteins (>40 kDa) require nuclear localization signals
  • four continuous basic residues (Lys and Arg)
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16
Q

During the secretory pathway, the signal recognition particle does what?

A

Binds to the ER-targeting signal and the ribosome during translation. It then wraps itself around ribosome-mRNA-peptide complex, tethering it to the ER membrane, thus halting its translation temporarily

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17
Q

What is Inclusion Cell Disease?

A

A disease characterized by a defective or missing GlcNAc phosphotransferase, and enzyme that adds M6P to lysosomal hydrolases.

No M6P tagged on lysosomal proteins

If the enzymes are not phosphorylated, they cannot be sorted into vesicles and delivered to lysosomes

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18
Q

Describe the clinical presentation of Inclusion Cell Disease

A

Failure to thrive, developmental delays, and physical manifestations such as hepatosplenomegaly and defective heart valves.

Death frequently occurs by age 7 due to congestive heart failure or recurrent respiratory tract infections

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19
Q

What is the function of chaperone proteins?

A

To protect large proteins and help fold into proper tertiary structure

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20
Q

Which heat-shock protein is ATP-dependent?

A

HSP60 (a chaperonin - barrel shaped compartment that catalyzes the folding of proteins via ATP)

21
Q

What is the function of proteolytic cleavage?

A

Converts inactive forms to active enzymes by uncovering active sites

Chymotrypsinogen to its active form, chymotripsin
Trypsinogen to its active form, trypsin

Also converts nascent precursor proteins to mature ones (i.e. proinsulin to insulin)

22
Q

What proteins are glycosylated during glycosylation?

A

Extracellular proteins (cell surface proteins and plasma proteins)

23
Q

What are the TWO types of glycoproteins involved in glycosylation?

A
  1. O-glycosidic (formed with hydroxyl groups of Ser or Thr)

2. N-glycosidic (formed with asparagine and sometimes glutamine)

24
Q

During acetylation, where are the proteins typically located?

A

Lysine residues

25
Q

During acetylation, histones are modified where?

A

N-terminal lysines. This is critical for gene regulation

26
Q

What enzyme catalyzes acetylation? What about deacetylation?

A

Acetylation is catalyzed by Histone Acetyltransferase (HAT)

Deacetylation is catalyzed by Histone Deacetylase (HDAC)

27
Q

Consequences of protein mis-folding include…

A

Generation of ROS, increased oxidative stress, disrupted neuronal signaling, disrupted ion homeostasis, calcium disregulation, disruption of energy homeostasis, inflammation, damage organelles, and breaks plasma membrane, leading to death.

28
Q

Define Familial Nuerodegeneration

A

Mutations that arise in specific genes.

Represents early onset forms of disease

29
Q

Define Sporadic Neurodegeneration

A

No known cause.

Represents late onset form of the disease, with brain aging being the common denominator

30
Q

What are the symptoms of Parkinson’s Disease?

A
  • rigidity and stiffness of limbs/trunk
  • tremors in hands, arms, legs, etc
  • slow movement
  • difficulties with balance, speech, and coordination
31
Q

What are some of the treatments available for Parkinson’s disease?

A

Dopamine replacement therapy (levodopa), deep brain stimulation, surgery, and stem cell therapy

PD is the result of the death. of dopamine producing cells, drastically decreasing available dopamine in the brain

32
Q

What is the area of the brain called that produces dopamine?

A

Substantia nigra

Iron and mitochondria rich area of the brain. In PD, the substantia nigra is excessively diminished.

33
Q

Parkinson’s disease is caused by the aggregation of what protein?

A

Alpha-synuclein (AS)

AS is a 14 kDa protein that is found in the cytosol and plasma membrane

34
Q

What happens when alpha-synuclein aggregates in PD?

A

Forms insoluble fibrils that deposit as Lewy bodies in dopaminergic neurons in the substantia nigra

35
Q

What are the signs and symptoms of Alzheimer’s Disease?

A
  • memory loss that disrupts daily life
  • confusion with time or place
  • difficulty understanding visual images and spatial relationships
  • misplacing things
  • changes in mood and personality
36
Q

What are the neuropathologic manifestations of Alzheimer’s disease?

A

Decreased size in memory and language areas of the brain

37
Q

Where on the neuron is plaque found?

A

Outside the neuron (extracellular)

38
Q

Where on the neuron is tau found?

A

Inside the neuron (intracellular)

39
Q

What peptide is formed and released that causes AD when misfolded?

A

Amyloid beta peptide (4.2 kDa) is generated and released into extracellular space.
Misfolded amyloid beta forms soluble oligomers and insoluble plaques

40
Q

What areas of the brain are most affected by Huntington’s Disease?

A

Basal ganglia and cerebral cortex

Progressive disorder caused by death of brain neurons

41
Q

What three primary aspects of brain function does Huntington’s disease affect?

A
  1. Behavior (psychiatric function)
  2. Movement (motor function)
  3. Thinking (cognitive function)
42
Q

HD is caused by a mutation in which gene?

A

Huntingtin gene (HTT) - codes for huntingtin protein

43
Q

Describe the Huntingtin protein

A

Large protein of 350 kDa localized in cytosol and nucleus

Function unknown, but appears to play important role in brain neurons

Involved in signaling, transport, binding, and protecting neurons from apoptosis

HTT knockout is lethal

44
Q

The HTT gene contains a trinucleotide repeat of what three base pairs?

A

CAG

Expansion of CAG triplet repeats leads to Huntington’s disease

45
Q

What is the relationship between the number of CAG triplet repeats to the age of onset of Huntington’s disease?

A

10-35 repeats: normal
40-50 repeats: adult onset
60+ repeats: juvenile onset

46
Q

What amino acid does CAG code for?

A

CAG codes for glutamine

Polyglutamine repeats in abnormal Huntingtin protein forms intramolecular H-bonds, which eventually misfold and aggregate

47
Q

Describe the neuropathology of Huntington’s disease

A

Atrophied striatum, basal ganglia, and ventricular dilation

48
Q

What are the signs and symptoms of Amyotropic Lateral Sclerosis (ALS)

A

Often begins with muscle twitching and weakness in a limb, or slurred speech
Eventually unable to move, speak, eat, and eventually breathe.

ALSO affects nerve cells in the brain and spinal cord, causing loss of muscle control

49
Q

Mutations in what cause ALS?

A

Mutations in Copper Zinc superoxide dismutase (CuZn SOD)

50
Q

Describe CuZn SOD

A

Enzyme responsible for dismutation of superoxide anion to hydrogen peroxide

Homodimer of 32.5 kDa

Mutations of SOD cause GAIN OF FUNCTION

Forms ROS and induces oxidative stress