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Lecture 14

MCD BIO 165A Lecture 14: lecture 14 proteasomesPremium

10 pages112 viewsFall 2018

Department
Molecular, Cell, and Developmental Biology
Course Code
MCD BIO 165A
Professor
arispe
Lecture
14

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Lecture 14
Proteasomes
Lysosomes destroy aging organelles (autophagy) & material brought into cell from
external environment
Proteasomes: eliminate abnormal proteins or degradation of individual
cellular proteins whose presence is no longer needed
- Not an organelle because no membrane; a micromolecular complex
- Required for elimination of protein that are misfolded and exported
from ER
These 2 share main response for protein elimination
overview
Both in cytosol & nucleus
Multiprotein complexes that consist of 4 rings of subunit stacked one on
top of the other with a cap at either end of stack
- B-subunit has promiscuous proteolytic activity
Assume a “barrel-shaped” form and are present in both the nucleus and cytosol
Degradation of protein carried out within hollow cylindrical space
- Labeled protein (poly-ubiquitin chain) binds to cap (ATPase), force generated by
ATP hydrolysis opens/closes cap & denatures protein
- Enter from cap, denatured -> linear, b-subunit recognizes peptide bond & clips it
- Small polypeptides released & recycled
- Uses ATP to drive conformational change in subunits (open/closing gates),
recognition of protein into proteasome chamber & protein denaturation, but not
needed for protein cleaving
Structure
Regulatory particle (RP)
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- 2 identical RPs, one at each end of core particle
- Each is made of several different proteins, many of which are ATPases
- 19S complex: cap = lid + base
- Rpn10 opens lid, requires ATP hydrolysis
- Some of the subunits have sites that recognize the small protein ubiquitin
Core particle (CP)
- 4 subunits/rings
- Made of 2 copies of each of 14 different proteins
- These are assembled in groups of 7 forming a ring; 4 rings are
stacked on each other like donuts
- A-subunits breaks disulfide bonds (main contributor to secondary
structure) -> denatures protein + dissociates other protein linked
non-covalently
- B-subunits function as proteolytic enzymes
Active sites face enclosed central chamber where degradation can
occur in a protected environment separated from the cytosol (makes
sure not cleaving everything indiscriminately)
Targets
Mainly endogenous proteins:
Transcription factors
- So that other transcription factors can take over
Cyclins
- Degraded to prepare for next cell cycle stage (checkpoints requiring elimination of
certain cyclins)
Proteins encoded by viruses & other intracellular parasites
Proteins folded incorrectly because of translation error or mutation
Sometimes proteasome produce peptides which are presented by major
histocompatibility complexes to generate antibodies -> recognize & destroy stuff
Conservation
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Proteasome Important for cell viability -> EK & bacteria have high proteasome
resemblance (except selective lid in EK; protein recognition)
Most conserved protein across species
Process
Protein destined to be degraded has to be labeled
with ubiquitin
- Ubiquitin covalently bound to protein,
specifically via Lys
- Other ubiquitins added to that ubiquitin
progressively, also via Lys
- Poly-ubiquitin chain binds proteasome cap ->
protein denatured -> cleaved -> amino acids
released from barrel
MG32 blocks proteasome function
- Blocks protein & proteasome binding
- Other molecules can also inhibit proteasome,
some beneficial to cancer
Degradation of unfolded proteins in ER
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