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Printable Handouts
Navigable Slide Index
- Introduction
- Lecture topics
- The ubiquitin-proteasome pathway
- Ubiquitin forms polymers with different linkages
- The proteasome: how is it constructed in vivo?
- Structure of the 26S proteasome (1)
- Structure of the 26S proteasome (2)
- Specific placement of 14 different CP subunits
- Stochastic self-assembly or chaperone-assisted
- The beta5 subunit is synthesized in precursor form
- The beta5 propeptide functions in trans
- Autocatalytic processing
- Overproduced beta7 subunit allows a bypass
- The beta7 C-tail is required for bypass
- High-copy beta7 drives beta-ring completion
- Model for 20S proteasome assembly
- Yeast Pba3 and Pba4
- Native PAGE analysis of yeast cell extracts
- Pba3/4 is required for proteasome assembly
- Pba3/4 and alpha3 subunit incorporation
- Deletion of alpha3
- Pba3/4 loss leads to 20S proteasome remodeling
- Conclusion
- alpha4-alpha4 confer a selective advantage
- Accumulation of altered 20S proteasomes
- Pba3/4 directs formation of a 20S proteasome
- Dedicated chaperones for the proteasome
- NAS2 identified as an extragenic suppressor
- Loss of Nas2 enhances the proteolytic defect
- Loss of Nas2 has a very weak effect on RP
- Nas2 co-purifies in a stoichiometric complex
- Rpt4-Rpt5 can assembly into 26S proteasomes
- Purification and LC-MS/MS of novel subcomplexes
- Multiple assembly chaperones (1)
- Synthetic genetic interactions between deletions
- Striking RP base assembly
- Multiple assembly chaperones (2)
- Is there a specific proteasomal RP pathway?
- Archaeal PAN ATPase homohexamer as model
- The PAN homohexamer is a trimer of dimers
- Structural features of PAN ATPase interfaces
- Eukaryotic ATPase heterohex. arrangement (1)
- Sites chosen for disulfide engineering
- The Rpt4 and Rpt5 ATPases interact directly
- Eukaryotic ATPase heterohex. arrangement (2)
- RP assembly model revisited
- Revision of assembly model
- Assembly chaperones for the proteasome
- Acknowledgements
Topics Covered
- The ubiquitin-proteasome system
- Proteasome composition and structure
- 20S proteasome core particle assembly
- 19S regulatory particle assembly
- Update talk: The ‘resolution revolution’
- Update talk: Proteasome regulatory particle assembly factor structure and function
- Update talk: Assembly factor inhibitors
- Update talk: Location of proteasome assembly in the cell
Talk Citation
Hochstrasser, M. (2022, March 30). Biogenesis of the eukaryotic proteasome [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved August 31, 2024, from https://doi.org/10.69645/VCCI9664.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Mark Hochstrasser, Consultant: Millennium Pharmaceuticals, Inc. (ad hoc consultant)
Update Available
The speaker addresses developments since the publication of the original talk. We recommend listening to the associated update as well as the lecture.
- Full lecture Duration: 64:24 min
- Update Duration: 8:52 min
A selection of talks on Biochemistry
Transcript
Please wait while the transcript is being prepared...
0:00
My name is Mark Hochstrasser, I am a professor at Yale University,
and I'm going to talk to you today about the biogenesis of the eukaryotic proteasome.
0:11
I will divide my lecture into four parts.
First, I will give you some background describing the basics of the ubiquitin-proteasome system.
Second, I'll describe the composition and structure of the proteasome.
Third, I'll talk about what we know about the assembly of the 20S core particle,
and lastly, I'll talk about assembly of the 19S regulatory particle,
the caps on the two ends of the core particle.
0:38
The ubiquitin-proteasome pathway provides
the major route by which many proteins in the eukaryotic cell are degraded.
The pathway can be divided into two essential phases,
the first being the tagging of a protein by ubiquitin,
this is an enzymatically-driven reaction requiring a series of enzymes.
Once a protein has been tagged with ubiquitin (and specifically a polymer of ubiquitins),
it can be recognized in the second phase of the pathway by the 26S proteasome,
a large protease complex that uses the energy of ATP to unfold the protein, after recognition of the poly-ubiquitin chain.
This drives the substrate into the core of the proteasome where
the peptidase active sites are located, which degrade the protein into short peptides,
and in the process, also recycle the ubiquitin rather than
degrading it, so the ubiquitin can be reused in further rounds of tagging.
1:32
The tagging of proteins by ubiquitin can have many different consequences.
Part of this versatility comes from the fact that not only
can a protein be modified by a single ubiquitin,
but in frequent cases it can be modified by polymers of ubiquitin.
In addition, the way that ubiquitins are connected to one another in the ubiquitin chain can vary.
Chains that are linked, for example, through lysine 48 in ubiquitin
(that's an isopeptide or amide bond),
those lysine 48-linked polymeric ubiquitin chains are
preferential targeting mechanisms for getting the protein to the proteasome.
In contrast, other kinds of chains have distinct functions in the cell,
for example, they're involved in endocytosis or DNA repair,
and are not necessarily involved in protein degradation.