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.
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.
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.
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.