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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.