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bio 310 > Proteostasis > Flashcards

Proteostasis Flashcards

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Biology 101 flashcards
1
Q

proteostasis

A

-protein and homeostasis

-coordinated cellular processes, regulating synthesis, folding, localization, and degradation of proteins

-regulates biological activities and health of cells

-consists of >1000 cellular components

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2
Q

protein coding review

A

primary structure= sequence of amino acids

secondary structure= alpha helices, beta strands

tertiary structure = fold helices and strands into domains

quaternary structure functional assemblies of chains (subunits)

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3
Q

molecular chaperones

A

-evolutionary ancient system

-prevents damaged or newly synthesized proteins from aggregating

-provides a microenvironment for refolding

-Molecular chaperones are a group of proteins that play a crucial role in assisting the proper folding, assembly, and stabilization of other proteins within a cell.

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4
Q

chaperones can help proteins to fold and refold to their ______ state?

A

Native

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4
Q

examples of molecular chaperones

A

Examples of well-known molecular chaperones include Hsp70 (Heat Shock Protein 70), which assists in the folding of nascent polypeptide chains, and Hsp90 (Heat Shock Protein 90), which is involved in the maturation and stabilization of a wide range of proteins, including many involved in cell signaling.

-HSP70 holds and releases hydrophobic segments of proteins

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5
Q

what are the protein misfolding states associated with neurodegenerative diseases?

A

amyloid fibrils, Amorphus aggregates, oligomers

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6
Q

true or false : chaperones lower the energy barriers to the native state and block the transition to undesired protein states

A

true!

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7
Q

chaperones facilitate protein folding in crowded cell

A
  • there are over 200 chaperones to deal with the diversity of protein folding

-every cell contains approximately 2 billion protein molecules

-chaperones can make up to 10% of a cells protein content

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8
Q

correct protein folding slows as protein ____ increases

A

length

with increasing protein length: there are more non-native (incorrect) contacts and more intermediate states

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9
Q

misfolded proteins directed to degradation pathways

A

-30% of newly synthesized proteins are degraded
-incorrect translation
-improper folding - many check points for some proteins

-failure to attain correct localization or integration with other proteins/cell components

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10
Q

protein misfolding can also occur over time due to:

A

-inherent protein stability

-protein activity

-environmental stress

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11
Q

major degradation pathways

A

1) ubiquitin-proteasome system (UPS)
-central role in maintaining cellular proteostasis by removing damaged or unwanted proteins, regulating protein levels, and controlling various cellular processes.

Ubiquitination: a complex pathway for tagging proteins for degradation
-The process begins with the covalent attachment of a small protein called ubiquitin to the target protein to be degraded. This modification is carried out by a series of enzymes:

E1 (ubiquitin-activating enzyme) activates ubiquitin in an ATP-dependent reaction.

E2 (ubiquitin-conjugating enzyme) receives the activated ubiquitin from E1.

E3 (ubiquitin ligase) facilitates the transfer of ubiquitin from E2 to the target protein. E3 ligases are highly specific and determine which proteins are tagged for degradation.

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12
Q

proteasomes two major functions?

A

-rapid degradation of misfolded proteins

-controlling half-lives of proteins

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13
Q

features of the proteasome

A
  • degrades up to 1/3 of newly synthesized proteins

-abundant ATP-dependent protease

-located in the cytosol

-consists of central cylinder (20s core) with 19s caps on each end

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14
Q

20S core/proteasome

A

-central hollow cylinder formed from multiple protein subunits

-assembled as a stack of 4-heptameric rings

-some subunits: distinct proteases, active sites face cylinder’s inner surface

-28 subunits (a7B7)

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15
Q

19S caps

A

-large protein complex

-17+ subunits (6 of which are ATPases)

-about 20 distinct proteins

-6 proteins hydrolyze ATP

-ATPases unfold proteins and move them into the 20s core for proteolysis

-primarily acts on ubiquitinated proteins

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16
Q

Ubiquitin

A

-76 aa protein

-contains 7 lysine residues

-polymerization of Ub occurs via Lys residues

-the function of Ub is different dependant on Lys residue used for polymerization

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17
Q

complexity of ubiquitination

A

E1= activating enzyme-, requires energy

E2 = conjugating enzyme, 30 structurally similar but distinct E2 enzymes

E3= ligase, 100’s of E3 enzymes, adds ubiquitin to protein
-humans have >500 E3 ligases

-E3 ligase largely determines the targeting of specific proteins

end result: targeting different degradation pathways
-UPS
-Autophagy pathways

18
Q

Autophagy

A

“self-eating,” which accurately describes the process by which the cell digests its own components. Autophagy is essential for cell survival, adaptation to stress, and the removal of toxic protein aggregates

19
Q

chaperone-mediated autophagy (CMA)

A

selective cellular process where specific proteins are targeted for degradation in lysosomes. Unlike general autophagy, which engulfs cellular components within autophagosomes, CMA involves the direct delivery of individual proteins to lysosomes. This process relies on chaperone proteins, such as Hsc70, that recognize specific target proteins with a CMA recognition motif.

20
Q

intercellular proteostasis

A

maintenance of protein homeostasis or proper protein function not just within individual cells but also within a broader multicellular context, typically within a tissue or an organism. It involves mechanisms and processes that help ensure the correct folding, trafficking, and degradation of proteins not only within a single cell but also in interactions between neighboring cells

21
Q

age-associated effects on proteostasis

A

-most neurodegenerative diseases show pathology involving specific and distinct protein misfolding events

22
Q

Alzheimer’s disease protein is called?

A

amyloid beta
Tau

23
Q

Amyotrophic lateral sclerosis protein is called?

A

TDP-43

FUS

24
Q

Huntington’s disease protein is called?

A

Huntingtin

25
Q

Parkinson’s disease protein is called?

A

alpha-synuclein

26
Q

prion diseases protein is called?

A

prion protein

27
Q

Proteolytic pathway conundrum

A
  • good vs bad proteins

-not precise

-estimated that a significant number of nascent peptides are degraded unnecessarily

28
Q

translational innacuracy

A

once every 10^3 to 10^4 codons

-estimated 18% of all proteins contain a mutation

29
Q

protein folding errors

A

protein aggregation
-amyloid formation

incomplete folding
-results in too little “active” protein being produced
e.g. phenylketonuriaa, p53

improper trafficking
-Tay-Sachs disease, familial hypercholesterolemia, CFTR

30
Q

what are the potential triggers/enhancers of misfolding?

A

-Post-translational modifications

-changes in protein-protein interactions

-mutation in protein sequence

-environment changes (pH, temperature, oxidative stress)

-instability in protein structure

31
Q

how might aging impact this proteostasis network?

A

As an organism ages, several factors contribute to the decline in proteostasis, leading to the accumulation of misfolded or damaged proteins and an increased risk of age-related diseases.

decline in chaperone function, accumulation of misfolded proteins

Molecular chaperones, which assist in proper protein folding, may become less efficient with age. This can lead to an increased likelihood of protein misfolding and aggregation, as chaperones may struggle to assist newly synthesized or damaged proteins.

Accumulation of Misfolded Proteins: Over time, misfolded or damaged proteins can accumulate within cells. These proteins are more likely to form aggregates that are resistant to degradation. Protein aggregates are often associated with age-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease.

32
Q

older cells have more?

A

-carbonylation
-oxidized methionine
-glycation
-cross-linking
-aggregates

all suggesting lost of function of proteostasis machinery

33
Q

what are protein aggregates?

A

are one of the most well-known types. They occur when proteins, either due to misfolding, denaturation, or other factors, accumulate and clump together.

they can disrupt cellular processes, interfere with proper protein function, and even lead to toxicity.

Examples include amyloid plaques in Alzheimer’s disease and Lewy bodies in Parkinson’s disease.

34
Q

age related declines in proteostatic network?

A

macro autophagy:
-reduced induction/nucleation
-accumulation of autophagosomes
-defective vesicular trafficking
-defective autophagosome maturation
etc.

Endosomal microautophagy
-accumulation of carbonylated proteins in MVB
-accumulation of lipid peroxidation products in MVB

chaperone-mediated autophagy
-decreased LAMP2a at the lysosomal membrane
-instability
-reduced lamp2a multimerization

lysosome
-decreases proteolytic activity
-lysosomal compartment expansion
-increases lysosomal protease (cathepsins)
-accumulation of undegraded materials
etc.

35
Q

aggregation

A

-mutated/destabilized proteins aggregate

-directly cytotoxic
-disruption of membranes
-interactions with cellular components
-increase demands on the proteostasis network
-titrate away components of this machinery

36
Q

pathway in healthy stresses, unstresses and aged individual

A

healthy unstressed: chaperones assist, folding is completed properly, the UPS/autophagy components and Ub/E3 ligase proteosome –> successfully degraded

healthy stressed: more chaperones required and more components needed

aged or diseased: fewer chaperones, fewer components and there is an accumulation of undegraded proteins and misfolded

37
Q

protein conformational diseases linked to aggregation

A

eye
-cataracts, retinal dystrophies

brain and nervous system
-Alzheimer’s
-Parkinson’s
-Huntington’s
-dementia
-ALS
-cerebral ataxia
-spongiform encephalopathies (prion)

muscle
-muscular dystrophy

kidney
-amyloidosis types

and many more

38
Q

stress, age and mutations contributed to?

A

increasing protein aggregation and declining proteostasis capacity

39
Q

why is protein folding so important?

A

proteins must be folded properly

signaling cascades

pathways down the road

40
Q

true or false: all proteins will eventually end up in the proteostasis degradation pathway?

A

true

41
Q

energy mapping

A

chaperones require energy to do their job correctly

42
Q

what is the primary pathway of autophagy?

A

formation of a phagophore

bio 310 (8 decks)

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