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Posts Tagged ‘heat shock protein’

Presenting….Hsp90 (chapter II, blogging in Just Science 08)

In Uncategorized on February 5, 2008 at 10:44 am

Chapter I gave an introduction into the role of Heat Shock Protein 90 (Hsp90) in evolution. The main point was its ability to mask/hide transforming mutations until needed in stressful times. This chapter describes its physical and biological properties.

Firstly, what the protein looks like. A really good introduction into Hsp90’s structure is found at the Sandwalk blog. Here’s a picture I stole (with permission) from his blog post on Hsp90:

Hsp90 structure
Picture from: Dollins, E.D., Warren, J.J., Immormino, R.M. and Gewirth, D.T. (2007) Structures of GRP94-Nucleotide Complexes Reveal Mechanistic Differences between the hsp90 Chaperones. Molec. Cell 28:41-56.

From Sandwalk: The complete protein is a dimer of two identical subunits. Each monomer has three distinct domains; an N-terminal domain (N); a middle domain (M); and a C-terminal domain (C). The ATP hydrolysis site sits at the interface between the N and M domains. The C domains interact to form the dimer. The presumed site of binding for misfolded proteins (“client” site”) is in the V-shaped pocket formed when the C domains come together. The mechanism of action of Hsp90 proteins is not known although it presumably involves a conformational change induced by ATP hydrolysis.

Secondly, it’s mode of action. Hsp90 works in concert with many other proteins to form protein-complexes ultimately activating the target protein. The molecular mechanism is as mentioned, still unresolved despite the presence of crystal structures. However, the following illustrations are taken from The Jackson Laboratory at University of Cambridge UK, to depict the overall events:

Model of the activation of a client protein by chaperone machines.
The chaperone Hsp70 system targets the client protein, in this case the steroid receptor, to the Hsp90 chaperone via the organising protein HOP which binds both chaperones. After transferring the steroid receptor to Hsp90, Hsp70 dissociates and is replaced by co-chaperones such as p23 and the high molecular weight immunophilin FKBP52. It is only in this complex that the steroid receptor is activated to bind ligand with high affinity.


And thirdly, which proteins does Hsp90 interact with. Again from The Jackson Laboratory:

Hsp 90 and Proteins it interacts with.
The abundant protein Hsp90 is thought to assist in the activation and assembly of specific proteins. Many of these proteins are critical for signal transduction and cell division. As a result, Hsp90 is a target for anti-tumour drugs.

Other examples are: PDK1, PKC-gamma, vSRC/cSRC, PPAR-alpha and p53. A comprehensive list of interacting proteins compiled by Picard Laboratory can be found here.

Thus, looking at all the proteins that can be affected by Hsp90, there is no surprise that the protein is highly conserved and that effects are profound when Hsp90 is fiddled with.


Revolution Evolution (chapter I, blogging in Just Science 08)

In Uncategorized on February 4, 2008 at 10:01 am

My contribution to JustScience 2008 will be a review on a protein with the potential to transform evolution theory as we know it today. The review will be divided into 5 separate blog posts:

1. Introduction to Hsp90 and evolution (this post)

2. Presenting the Hsp90 protein

3. How can chaperones act in evolution

4. Evidence for Hsp90 involvement in rapid evolution of new traits

5. Summary

Here’s the teaser: In one generation you can go from this

Drosophila wild type

to this (a hopeful monster ?).

Hsp90 reduced expression in drosophila
(from Rutherford SL and Lindquist S, Nature 1998
, to see more “monster”-pictures, do a google image search on Hsp90 and evolution)

The protein in focus, Heat Shock Protein 90, is otherwise as normal as a protein can get. It is ubiquitously expressed in all cells and across species, and its function is the same as other heat shock proteins, it’s a chaperone.

A chaperone is a protein that helps other proteins fold correctly (or prevents them to aggregate into non-functional protein junk). Without the chaperone the protein would not achieve an active conformation and end up being degraded. For an excellent video illustrating chaperone assisted protein folding go here.

Caperone illustration
Illustration of chaperones in action. Picture from Nurse Minerva

Now, it turns out that the Hsp90 chaperone function is important for development and evolution of new traits. To illuminate this, the first paper I will discuss is from 1998 by Susan Lindquist’s lab at the Whitehead Institute.

In this paper they take fruit flies and reduce the expression of Hsp90. As I shall come back to later, this is the experimental equivalent to a stressful condition (like for instance high temperature). They can’t knock out Hsp90, because a complete lack of it is not compatible with life (which demonstrates the importance of this protein). When Hsp90 levels are reduced, the fruit flies are born with a number of different defects ranging from defects in the legs and bristles to defects in the eye (see image above). Now, this could be expected when knocking out a protein, but such extensive morphologic changes are not expected from just reducing the levels of a protein (unless maybe if it’s a transcription factor, which it isn’t). The hypothesis explaining this goes as follows……Since Hsp90 is a heat shock protein it is helping other proteins fold. When stressful conditions occur, there will be more proteins that are in need of folding-help, thus some of the proteins that under normal conditions got their help from Hsp90 will now be left on their own. Since, under such conditions, you see these extensive morphological changes, these proteins must be doing something out of the ordinary when on their own, or if they aggregate, their absence causes abnormality. The theory states that these in-need-of-help-proteins must have accumulated mutations that potentially causes abnormality, but under normal conditions they are still able to perform normally due to the action of Hsp90. The implications for evolution are breathtaking since this means that an organism can accumulate a number of mutations and still function normally, but when exposed to stressful conditions, the changes at the protein level are suddenly exposed in their offspring and appear as physical abnormalities. This allows for extremely rapid evolution and could potentially enable a species to change in just a couple of generations.

Illustration of the process and further evidence for this theory will be presented in the next 4 posts the next 4 days, in SciPhu for just science 08.