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My name is Jeffrey Brodsky, I'm a
professor at the University of Pittsburgh.
Before I embark on this formidable topic,
there are several things
I need to point out.
First, this is a broad topic and therefore
it's important to start with some basic
paradigms that drive our understanding
of how molecular chaperones function in
cells and how certain human diseases
arise, either from defects in molecular
chaperones, or how chaperones
impact the ability of certain human
diseases to evolve over time in
patients with those diseases.
I'd like to begin with a certain myth that
I think is commonly held in the field of
biological sciences.
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The myth is that proteins
can fold on their own.
In other words, all the information
required for protein folding is contained
within the primary amino acid sequence
of that protein or polypeptide.
This myth is actually true when
experiments are performed in vitro,
because classic studies from Anfinsen and
colleagues showed that unfolded or
denatured polypeptides in the test
tube could refold on their own,
assuming that the conditions had been
optimized in that in vitro reaction.
1:13
In truth, the cell is a brutal place for
a protein to fold,
the cell has not necessarily been
optimized to engineer or to allow
efficient protein folding to take place,
and the reasons for this are as follows.
First of all, there's a very high
concentration of proteins in the cytoplasm
of cells, which by and
large represents the major compartment
in which protein folding occurs.
Second, the cell is exposed
to various stresses and
these stress conditions can compromise the
ability of proteins to fold efficiently.
Stresses include heat, oxidizing damage,
denaturants and other chemical
insults such as heavy metals,
that reduce protein folding efficiency.
In addition, there are spontaneous and
inherited mutations in polypeptides that
can arise, and this can significantly
reduce the efficiency of protein folding
in the cell, something that's not
encountered in the test tube.
