Is this how the two ends of Hsp70 communicate?
Crystallography will test whether the ATP-binding end
(shown in blue with a red nucleotide bound) indeed pries
open the protein-binding end (shown in orange with one
alpha-helix held open).
As any cook knows who has boiled an egg or splashed lemon
juice in a cut, our proteins are liable to damage by heat, acid
and other insults.
The body has a host of "molecular chaperone" proteins which
alleviate such damage.
Failure of this protection underlies many diseases, from
genetically inherited cystic fibrosis to age-related
Alzheimer's.
To better understand the body's native protective system, Dr
Sigurd Wilbanks in the Department of Biochemistry within the
Otago School of Medical Sciences is studying a molecular
chaperone named Hsp70.
A central technique for Dr.
Wilbanks's work is X-ray crystallography.
Ever since X-rays were first used to give an
atomic-resolution picture of a protein's three dimensional
structure in 1953, such structures have been powerful tools
for understanding how proteins function as molecular
machines.
Although indirect studies (What drugs inhibit this protein?
What does it do with unusual substrates?) are informative,
only structures give a physical context for synthesising
other information.
For even a simple machine like an office stapler, knowing its
three-dimensional structure makes it much easier to
understand how it works.
The same is true of proteins - X-ray crystallography of
proteins was the key to three of the last seven Nobel prizes
in Chemistry.
Other labs used this technique to show how one end of Hsp70
can grasp a protein which has lost its correct structure but
might still be "re-folded" into its correct shape.
Re-folding into the correct shape requires ATP, the same
energy currency which drives muscles.
While a post-doctoral fellow at Stanford University, Dr.
Wilbanks solved structures of the other end of Hsp70, showing
how it extracts energy from ATP.
Despite much international effort, there is not yet a picture
of how the energy from ATP at one end of Hsp70 contributes to
refolding at the other end.
X-ray crystallography requires crystals and it proved very
difficult to prepare crystals of both ends of Hsp70 together.
Results from Dr.
Wilbanks's masters and honours students over the last four
years inspired a guess about the structure of Hsp70.
In turn, this informed guess let Dr.
Wilbanks and collaborators in Heidelberg, Germany engineer a
version of Hsp70 which crystallises and will show if the
guess was correct.
A new grant from the Bequest Funds of the Otago School of
Medical Sciences will allow the lab to prepare more of these
crystals and to analyse them in the Otago Macromolecular
X-ray Diffraction Suite in the Department of Biochemistry.
It also provides for travel to the Australian Synchrotron.
The University of Otago is a founding member of the
consortium which maintains a high powered X-ray beam and
protein diffraction facility at this government facility in
Melbourne.
A three-dimensional picture of how the two halves of Hsp70
communicate will underlie design of drugs to stimulate the
body's molecular repair abilities.
They will never be able to prevent an egg from becoming
hard-boiled on the stove, but stimulation of molecular
chaperones can slow the damage which leads to Alzheimer's and
other neurodegenerative disease.
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