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Printable Handouts
Navigable Slide Index
- Introduction
- The structure of the 26S proteasome
- Three active sites of the 20S proteasome
- Proteasome inhibitors
- PS-341
- PS-341 in hematological cancers
- Proteasome inhibitors in multiple myeloma
- Archaeal and eukaryotic proteasomes
- ATP-dependent steps in proteasome function
- The gated channel of the 20S proteasome
- HbYX motif is critical for ATP-ring binding
- The role of peptides from PAN’s C-terminus
- X-ray diffraction of the proteasome
- X-ray diffraction and cryo-EM
- Conformational change in α-subunits (before)
- Conformational change in α-subunits (after)
- The open and closed conformations review
- Prions inhibit the proteasome function
- PrPSC inhibits proteasome function
- Inhibition assays with agg. β-PrP and PrPSc
- Non-toxic PrPs do not inhibit 20S proteasomes
- Ub-conjugates activate the 26S proteasome
- Poly-Ub-conjugates stimulate gate-opening
- Only poly-Ub proteins stimulate peptide hydrolysis
- Ub conjugates stimulate 26S ATPase activity
- Ub conjugates activate their own degradation
- Proteasome activity and USP14 inhibitor
- Inhibition of USP14 enhances tau degradation
- Animation of the proteasome activity
- Points to remember
- Acknowledgements
Topics Covered
- The 26S proteasome
- The 20S proteasome
- Proteasome inhibitors
- PS-341
- Proteasome inhibitors in multiple myeloma
- Structures of the archaeal PAN ATPase-20S complex and the eukaryotic 26S proteasome
- Multiple ATP-dependent steps in proteasome function
- The gating mechanism of the proteasome
- Prions inhibit proteasome function
- Binding of ubiquitin conjugates activate the 26S proteasome by stimulating 20S gate-opening and ATP hydrolysis
- Ubiquitin conjugates activate their own degradation by the 26S Proteasome
- The inhibitor of proteasome-associated deubiquitinating enzyme Usp14, IU1, enhances degradation of tau
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Talk Citation
Goldberg, A. (2014, October 7). Protein degradation and defense against neurodegenerative disease 2 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 7, 2024, from https://doi.org/10.69645/PYAG1915.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Alfred Goldberg has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Protein degradation and defense against neurodegenerative disease 2
Published on October 7, 2014
42 min
A selection of talks on Neuroscience
Transcript
Please wait while the transcript is being prepared...
0:04
In this lecture, I want to
focus on the functioning
of the 26S proteasome.
This has been an exciting
area of recent research
and is of increasing
importance in our understanding
of neurodegenerative disease
and biology, generally.
This side illustrates
the major components
of the ubiquitin proteasome pathway
using the cryo-EM, single particle
EM, from the laboratory of
Wolfgang Baumeister in Munich.
Proteins are actually
degraded within the core
20S proteasome shown here in yellow.
The degradation occurs within
a very tight protein coat.
Shown by the scissors,
there are six active sites
that cleave after hydrophobic,
basic or acidic residues
in an isolated compartment
away from the cytosol.
However, for proteins to be injected
into the core 20S proteasome,
they have to be generally
ubiquitinated and bind to the 19S
regulatory complex
shown here in blue.
This has the receptors
for the ubiquitin chain
and also contains six
ATP-hydrolyzing sub units that
carry out the unfolding of
substrates and their translocation
into the 20S proteasome
for degradation.
And we are now able to
explain these processes
at near-molecular understanding.
They also have important
relevance to human disease
which I'd like to discuss.