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Printable Handouts
Navigable Slide Index
- Introduction
- Cells have numerous compartments
- Cellular protein synthesis and maturation (1)
- Cellular protein synthesis and maturation (2)
- Quality control pathways monitor biosynthesis
- Protein localization is also monitored for failures
- In vitro ER protein translocation analysis (1)
- In vitro ER protein translocation analysis (2)
- A mislocalized protein is ubiquitinated in vitro
- Mislocalization existence & consequences (1)
- Mislocalization existence & consequences (2)
- Chronic mislocalization causes disease
- Mislocalized proteins recognition & degradation
- Bag6 complex binds to mislocalized proteins
- Bag6 facilitates ubiquitination
- Bag6 - protein targeting machinery
- SRP; co-translationally. Bag6; post-translationally
- Bag6 recruits a ubiquitin ligase (1)
- Bag6 recruits a ubiquitin ligase (2)
- How Bag6 monitors the cytosol
- Lessons from Bag6 quality control
- Not all is as simple as it seems…
- Post-translational membrane protein pathway
- Bag6 is embedded within the targeting pathway
- Bag6 degrades mislocalized membrane proteins
- Fate of mitochondrial membrane proteins
- Reconstitution of mitochondrial targeting & failure
- In vitro synthesized protein is insertion competent
- A protein is ubiquitinated if it fails targeting
- Reconstitution of mitochondrial targeting & failure
- Ubiquilins are abundant TMD binding partners
- Ubiquilins & Bag6: similar & different specificities
- Reconstitution of mitochondrial targeting & failure
- Ubiquilins are abundant TMD binding partners
- Ubiquilin is sufficient to maintain solubility
- Ubiquilin-Omp25 complex is insertion competent
- Ubiquilin can facilitate Omp25 insertion in vitro
- Analysis of Omp25 in Ubiquilin knockout cells
- Other proteins in ubiquilin knockout cells
- Ubiquilins' clearance of non-targeted proteins
- The UBA domain recruits ligase
- Ubiquitination precludes insertion
- Cytosolic surveillance by ubiquilins model
- Degradation pathways of mislocalized proteins (1)
- PolyQ aggregates can sequester UBQLNs (1)
- PolyQ aggregates can sequester UBQLNs (2)
- Flow cytometry assay for UBQLN function
- PolyQ aggregates sequester & impair UBQLNs
- Degradation pathways of mislocalized proteins (2)
- Where is the future of protein quality control?
- Thank you
Topics Covered
- Protein maturation is monitored for failures
- Failures of protein localization in vitro and in vivo
- Mislocalized proteins are selectively recognized
- Relationship between protein maturation & quality control
- Mitochondrial proteins are also prone to mislocalization
- Recognition of mislocalized mitochondrial proteins
- Protein aggregates can disrupt protein quality control
- Key concepts and the future of protein quality control
Talk Citation
Hegde, R. (2017, March 29). Quality control of proteins mislocalized to the cytosol [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 22, 2024, from https://doi.org/10.69645/UWZD9777.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Ramanujan Hegde has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Methods
Transcript
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0:00
My name is Manu Hegde.
I'm a group leader
at the MRC Laboratory
of Molecular Biology
in Cambridge, England.
And today, I'm going to talk about
Protein Quality Control.
The goal of this lecture
is twofold.
First, I want to introduce you
to the concept
of protein quality control
and tell you a bit about
why it's important.
Second, I want to tell you
not just about what we know
but a little bit about
how quality control processes
are studied experimentally
and how we've come to learn
what we know today.
0:30
A good place to start
for any discussion
on protein quality control
is to consider
how incredibly complex
the inside of a cell is.
So what you're seeing
on this slide right now
is a textbook picture
of the inside of a liver cell,
and this is viewed
by electron microscopy.
And what you can see
is how incredibly compartmentalized
the cell is,
so there are lots
of different compartments
that you can see, for example,
I've labeled
the endoplasmic reticulum in green,
mitochondria in red,
peroxisomes in blue and so forth.
And all of these compartments
have unique complements of proteins
and these proteins of course
give these compartments
their unique functional properties.
1:10
A consequence of having
all of these
proteins compartmentalized
is that these proteins need
to be constantly replenished
and this is
particularly important in cells
that are rapidly growing
or dividing.
But in all cells, proteins
constantly are replenished.
So what that means
is that the ribosome
of which there are many millions
per cell
have to synthesize new proteins
and they do so at a rate
of approximately one protein
every one or two minutes.
And these new proteins
then have to be taken
to all the different compartments
that I just told you about
where they have
to be folded properly,
assembled,
associated with cofactors,
and finally achieve
a functional state.