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Printable Handouts
Navigable Slide Index
- Introduction
- DNA to proteins - happy endings
- DNA to proteins - reality
- Life degrades
- Ubiquitin-proteosome pathway degrades proteins
- Stability of cFos and cMyc
- NF-kappa B activation
- The cell cycle
- Abnormal proteins rapidly degrade in cells
- Neurodegenerative diseases with inclusion bodies
- Protein folding diseases
- How not to store a protein (1)
- How not to store a protein (2)
- Two major proteolytic pathways in cells
- Major enzymic activities of lysozymes
- Pathways of degradation by lysozymes
- The ubiquitin-proteosome pathway
- 3D structure of ubiquitin
- Formation of the isopeptide bond
- Ubiquitination
- Ubiquitin conjugation to protein substrates
- Action modes of E3 ubiquitin ligase
- F-box E3's
- Ubiquitin-proteosome pathway - 26S proteasome
- The 26S proteosome
- Eukaryotic 20S proteosome
- 26S proteosome structure
- PAN-20S and 26S comparison
- Protein gate in the proteasome
- Unfolding of GFPssrA
- PAN promotes ATP-dependent degradation
- Proteosomes degrade proteins processively
- Multiple roles of ATP
- Proteins enter, peptides diffuse from the particle
- The cellular chamber of doom
- 20S proteosomes have 3 types of active site
- Proteosome inhibition by MG132
- Proteosome inhibitors
- PS-341: in vitro activity
- Effect of PS-341 on 3H-thymidine
- Complete response to PS-341
- Mammalian cell protein breakdown pathways
- Two pathways for antigen presentation
- MHC class 1 antigen presentation pathway
- Proteosome subunit changes with interferon
- Steps involved with protein degradation
- Life degrades - conclusion
Topics Covered
- Protein levels in cells are regulated by their rates of synthesis and degradation
- Regulatory proteins are rapidly degraded by the ubiquitin-proteasome pathway
- Examples include many oncogenes, transcription factors and cyclins which control progress through the cell cycle
- NF-kappa B activation in disease depends on degradation of the inhibitor, I-kappa B
- Misfolded or mutant proteins are rapidly degraded
- Neurodegenerative and protein folding diseases
- Two major proteolytic pathways exist in mammalian cells
- Many acid hydrolases exist in lysosomes
- Endocytosed proteins and those in autophagic vacuoles are degraded in lysosomes
- The ubiquitin-proteasome pathway
- 3D structure of ubiquitin
- Formation of the isopeptide bonds during ubiquitin conjugation to proteins
- The ubiquitin-proteasome pathway
- Proteasome function is linked to ATP hydrolysis
- Proteasomes unfold proteins and translocate them into 20S particles
- Three types of peptidase sites
- Proposed mechanism of proteasome inhibitors
- Therapeutic applications of proteasome inhibitors
- Two systems for protein breakdown function in the two pathways for antigen presentation
- Changes in proteasome subunits induced by interferon
- Steps involved in generating antigenic peptides
Links
Series:
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Therapeutic Areas:
Talk Citation
Goldberg, A. (2016, January 19). Protein degradation [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 21, 2024, from https://doi.org/10.69645/CRIB7140.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.
A selection of talks on Biochemistry
Transcript
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0:00
In today's lecture, we're going to be discussing the cellular mechanisms for
degrading intracellular proteins and the biological importance of this process.
Thus far in the course,
you've been concerned with systems for expression of genetic information.
The central dogma of modern biology is shown in the next slide.
0:22
This slide emphasizes that cell proteins are being
made off messenger RNA molecules encoded in DNA.
And the general assumption until recently was once proteins are made,
they are stable structures that basically live happily ever after.
Today we'd like to disabuse you of
this comfortable idea and replace it with another view of the cell.
0:47
This revised view emphasizes that proteins,
once synthesized, are short lived structure.
Their lives are nasty, brutish and short.
And this rapid destruction of cell proteins,
although seemingly highly wasteful,
is absolutely essential for viability.
1:07
As this slide's title implies,
we believe that protein breakdown is absolutely essential for viability.
In fact, this image is the official T-shirt on
my laboratory and it is sort of our philosophy of the research we do.
Specifically, what is shown here are
these complex molecular machines that are
responsible for the continual degradation of protein.
The large 26S proteasome shown on the left,
the core 20S proteasome particle inside which proteins are degraded on the bottom,
the form found in eukaryotic cells.
And on the top, the simpler symmetric proteasomes that are found in prokaryote.
Prokaryotes and mitochondria also have
other energy dependent proteolytic machines such as
the HslVU Complex which is a cousin of the proteasome,
a simpler earlier precursor.
But today we're going to focus on the process in the eukaryotic cells.
I would like to ask the very fundamental question.
First of all, of why cells degrade so rapidly many proteins?
It turns out that the most rapidly hydrolized proteins are among the most important,
the sexiest proteins in contemporary biology.
This slide shows a list of many of the most important proteins in the regulation of