Proteins are highly organised structures: they're folded into particular conformations;associated with other protein subunits and have different levels of organisation (see previous post).
But how do they achieve their folded state?
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| (1) How do proteins fold? |
We all like
help-so do proteins
Sometimes it is easier when someone helps you fold away your
clothes. Same for proteins-yes they are largely self-folding. But what happens
when this goes wrong?
Chaperones are part of the cell’s emergency services attending various accidents (misfolded proteins) but in a
disaster they all flood to the scene (when a cell is under stress).Many chaperones are heat shock proteins (Hsp) and are highly abundant when a cell is under stress (during nutrient starvation, extreme temperatures, exposure to toxins etc).
Aggregates can easily form when hydrophobic regions of the
protein can end up on the outer surface of the misfolded or partially folded
protein and will attract other misfolded proteins with exposed hydrophobic
residues (as the cell has an aqueous environment the water fearing residues
want to bury themselves in the core of a protein). In a living cell it not just empty space
(imagine trying to fold your washing in a crowd without elbowing anyone!). Chaperones help the protein
fold in the most energetically favorable way as well as preventing the
unwanted binding of other proteins during the folding process.
Some molecular chaperones (Chaperonins-Hsp60) act like a huge tent
in the middle of the crowd where you can fold your washing without people
getting in the way. They completely isolate the protein from the environment of
the cytosol.
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| (2)Bacterial Hsp60 (GroEL) and associates Hsp10 (GroES) |
Whilst other chaperones (Hsp70) bind to a region of the
protein to aid folding like having a group of people who are designated to aid
in folding of washing-it is their job.
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| (3) Hsp70 binds to hydrophobic regions to aid folding |
Chaperones are not just involved in folding they’re also
important for unfolding, refolding and trafficking. Chaperones work by an ATP* dependent mechanism:
they bind to hydrophobic regions of a misfolded (non-native) protein.
One size of chaperone doesn't fit all:
There are different classes of molecular chaperones (they are usually classified by their molecular weight). Hsp60 (chaperonins) ,Hsp70,Hsp90 and Hsp100 systems. The numbers indicate the molecular mass of each Hsp protein subunit.
There are different classes of molecular chaperones (they are usually classified by their molecular weight). Hsp60 (chaperonins) ,Hsp70,Hsp90 and Hsp100 systems. The numbers indicate the molecular mass of each Hsp protein subunit.
Focusing on the chaperones involved in protein
folding: namely- Hsp60,70 and 90.
They generally act under two systems Hsp70 and Hsp60 (chaperonins).
They generally act under two systems Hsp70 and Hsp60 (chaperonins).
Hsp70 interacts with newly synthesised proteins and releases
them . Whilst chaperonins (Hsp60) are
large cylindrical protein complexes ( figure 3) (composed of several polypeptide
chains-quarternary structure: an outfit (see previous post)).They enclose the
proteins for folding. The two systems act sequentially Hsp70 act on newly
synthesised proteins and then chaperonins assist folding of proteins that do
not reach their correct folded state by Hsp70 alone.
So imagine you (Hsp70)are folding your washing and your Mum
(Hsp60) is stood by your side and when something is difficult to fold or you
have not folded it correctly your Mum takes over to ensure correct folding.
The Hsp90 system functions downstream of Hsp60. It acts
in the late folding stages of proteins involved in cellular signalling and
development. Both Hsp70 and Hsp90 can direct proteins for degradation.
It is now like your Grandma (Hsp90) has joined the folding party;
smoothing out the creases of odd item that your Mum (Hsp60) has missed.
Folding avoids
creases but what does it mean for proteins?
When proteins fold they gain a particular shape which is
important for the function of that protein. It may allow it to associate with
other proteins to form a complex.
It has been suggested that the decline in the cell’s ability
to correctly fold proteins and maintain correct protein folding (proteostasis)
declines with age. This can allow the formation of protein aggregates which are
involved in many neurodegenerative diseases such as Alzheimer’s and Parkinsons
disease. Finding out more about chaperone mediated surveillance of proteins is
vital as these diseases become more prevalent in our aging society.
*ATP= Adenosine triphosphate is the energy currency of the
cell. It is a phosphorylated nucleotide that is made and consumed by all cells
and drives chemical reactions
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| (4) Comparison of a healthy neuron with a Alzheimer's neuron with protein aggregates ( Beta amyloid plaques and neurofibrillary tangles) |
References
Hartl F, Bracher A, Hayer-Hartl M., 2011. Molecular chaperones in protein
folding and proteostasis., Nature reviews.,
475., pp324-332
Lodish H et. Al., 2008., 6th Ed., Molecular cell biology., W.H.Freeman.,
New York
Saibil H., 2013. Chaperone machines for
protein folding, unfolding and disaggregation., Nature reviews., 14.,
pp631-632
Images
Right: http://ocw.mit.edu/courses/biology/7-343-protein-folding-misfolding-and-human-disease-fall-2004/
