Monday, 21 January 2008

Structure and mechanism of Hsp90, a heat shock protein

Heat shock proteins are over-expressed when cells are exposed to heat or stress. Their function is to help other proteins to fold "correctly" into their mature, functional forms and, as such, they are classified as "chaperones". The structures and functions of these proteins will be described in much more detail in section 8 of the PPS course ("The Protein Lifecycle").

Today (21 January), in the School of Crystallography's Monday seminar programme, Maruf Ali from the Institute of Cancer Research in London spoke about his research on the structure of the heat shock protein Hsp90. This protein is found in all kingdoms except for the Archaea; it interacts with many other proteins (known as "client proteins" to help them enter their mature, active structural forms. Hsp90 client proteins include kinases that are important targets for anti-cancer drugs - hence the ICR's interest.

Hsp90 is a three-domain protein. The N-terminal domain binds ATP, which is necessary for the protein's activity; the middle domain binds client proteins; and the C-terminal one is involved in dimerisation. Structures of each domain separately were already known when Maruf started his post-doc a few years ago; each of these domains has a fold in Scop's alpha+beta class. Maruf's work involved solving the structure of a mutated form of the intact protein bound to a co-chaperone, (Ali et al. (2006), Nature 440, 1013-1019; PDB code 2CG9). This structure gives a clear picture of a complex structure, showing how a "lid" of structure closes to enabl the client protein to bind, and supports a previously proposed model in which the N-terminal domain is also involved in dimerisation.

Try downloading the structure, loading it into Jmol or a similar program, and seeing if you can identify the three domains.


Philippe said...

From the structure I was able to color each of the 4 chains (A,B,X,Y). Where can we found the informations about the domain coordinates? I am sure that these informations are on the Nature paper I tried to find on Athens, but neither on Science direct we do not have access to this journal, where I am sure the coordinates of the three domains are. Any body has tips on this?

Dr Clare Sansom said...

Hello Philippe and everyone,

Thanks for this and your email. I admit that the domain structure of this protein is confusing, but I have now worked out exactly what is going on.

In all the domain databases (Pfam, Smart etc) Hsp90 is described as a two domain protein, because the "middle segment" and the C-terminal domain are classified together as a single domain. The Nature paper describes the domain structure in detail. Residues 1-216 form the N-terminal domain, the "middle segment" (or domain) residues 273-525, and the C-terminal domain the rest of the protein. And, just to add confusion, the very C-terminal end of the C-terminal domain - residues 678-709 - are disordered, and therefore not observed in this crystal structure.

I hope this helps you identify the functional parts of the protein in the structure. Good luck!

Best wishes