Pressure and protein aggregation.

Laszlo Smeller 

Semmelweis University of Medicine, Institute of Biophysics and Radiation Biology, Budapest, Hungary


Denaturing effect of pressure is well known. The influence of pressure on intermolecular forces became interesting topics only recently, when the role of protein aggregates in the development of conformational diseases was established.
Another approach to the aggregation comes from the protein folding problem. It was already clear in the study of disease related aggregation, that correctly folded proteins cannot form aggregates, unless there is a serious destabilizing factor, lowering the stability of the native state. From the point of view of the folding, aggregation can occur among the misfolded proteins.
Pressure is used in study of protein aggregation for two reasons. First we used pressure unfolding to be able to study the refolding. The second aim was to study the effect of pressure on the intermolecular forces, by pressurizing protein aggregates of different kind.
Our studies show that refolding of the pressure unfolded protein can only be partial. Apart the folded protein molecules, a significant amount of molecules with intermediate conformation is formed. This effect has been demonstrated for several proteins including myoglobin, lipoxigenase, lysozyme, indicating the general feature of this behavior.In case of horseradish peroxidase the destabilized intermediate was however detected only if the disulfide bridges were cleaved prior to the pressure treatment.
Pressure induced dissociation of oligomers is known. This would suggest pressure-disaggregation. Our observations indicate that the aggregation process consist of several successive steps, which are probably governed by a very slow kinetics. The few first steps of this aggregation process can be reversed by pressure, but the well formed (probably restructured) aggregates persist the pressure treatment.
We suggest a new phase diagram containing metastable states, that expands the capabilities of the conventional elliptic T-p phase diagram of the proteins in order to explain aggregation phenomena.


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Presentation: invited oral at E-MRS Fall Meeting 2003, High Pressure School 2003 (5th), by Laszlo Smeller
See On-line Journal of E-MRS Fall Meeting 2003

Submitted: 2003-05-14 17:03
Revised:   2009-06-08 12:55