The Svedberg Award 2010
Per Jemth
Associate professor and group leader at the
Department of Medical Biochemistry and Microbiology,
Uppsala University.
A committee consisting of members from the SFBM and Swedish National
Committee for Molecular Biosciences boards has decided to propose
Per Jemth to the Svedberg Award 2010 for his "Important
contributions to the understanding of the interplay between protein folding and
peptide-protein interactions in cell membrane protein organization."
The award of SEK 35 000 together with the medal and diploma was presented at
the FEBS congress in Göteborg on 26 June-1 July 2010.
Presentation of
Jemth's research
Background
When I started my chemistry studies in Uppsala,
I was favouring inorganic chemistry, possibly because of reading popular
physics. But, I realized after a while how exciting the chemistry of life is and
by the time I received my MSc in 1994, I knew biochemistry was what I wanted to
do. I joined Bengt Mannervik’s group at Uppsala University for my PhD studies.
Here, I worked on three different types of enzymes, mainly on glutathione
transferases but also on glyoxalase I and glyoxalase II. Enzyme kinetics was my
main tool and I used it to dissect enzyme mechanisms and the role of
conformational changes in catalysis. I also ventured into enzyme evolution,
which is a major area of research in Bengt’s group.
In my first postdoc (2000-2002) I changed scientific field to start working on glycobiology with Ulf Lindahl at the medical faculty at Uppsala University. It was widely believed in the glycobiology field that the glycosaminoglycan heparan sulfate contained a “code”, much like DNA. This view emerged from the very specific antithrombin-“heparin pentasaccharide” interaction, which Ulf and his coworkers successfully developed into the drug Fragmin. In my work I designed heparan sulfate oligosaccharide libraries and purified and sequenced a large number of saccharides and used these to assess ligand and substrate specificities for enzymes involved in biosynthesis of heparan sulfate as well as proteins known to interact with heparan sulfate. I did not find any evidence for specific interactions and from these experiments a new view emerged that most heparan sulfate-protein interactions are non-specific and mainly related to the overall charge of the molecule. The specificity of heparan sulfate-protein interactions is still a vexing issue in the field.
After this postdoc I looked for a new challenge and found it in protein folding. Up to then my knowledge about this absolutely fundamental aspect of protein science was close to zero and I was therefore happy to go to Cambridge, UK, on a long-term EMBO fellowship for two years to learn about protein folding in Alan Fersht’s lab. Here, I contributed to another controversial issue, the role of intermediates in protein folding. We found evidence for a productive intermediate in a small protein domain and also characterized the structure of the transition state for the folding reaction of this protein. Except for a solid knowledge in protein folding I found a long-term collaborator in Stefano Gianni, another postdoc in Alan’s group.
With this background, I came back to Sweden and the Department of Medical Biochemistry and Microbiology, Uppsala University, in 2004 with the aim of combining the different aspects of biochemistry I have worked on, into novel projects and ideas. My current position is a “forskarassistenttjänst” funded by the Swedish Research Council.
Current research
There are two main projects in the lab. (1) folding,
binding and allostery in protein-ligand interactions, and (2) oncogenic proteins
from human papillomavirus.
(1) Folding, binding and allostery in protein-ligand interactions
One main aim is to address and answer the question: What is the relation between protein dynamics and function? The role of dynamics in protein function is currently a very hot topic in protein science. I here use the word “dynamics” in its widest sense, that is, it could be combined folding and binding of intrinsically disordered proteins to tiny and even transient rearrengements of the folded polypeptide. Yet, there is still a paucity of experimental data regarding many aspects of how dynamics actually influence the function of proteins. In my lab, we want to test current hypotheses regarding protein dynamics and address unanswered questions with experimental data. We also want to understand the most flexible functional polypeptides: intrinsically disordered proteins.
(2) Oncogenic proteins from human papillomavirus.
Cervical cancer is very common in the world with half a million new cases per year resulting in the deaths of more than 200,000 women. Infection by high-risk strains of human papillomavirus (HPV) is the cause of cervical cancer. A salient feature of HPV induced cancer is the continued expression of the two major viral oncoproteins, E6 and E7. We want to understand the molecular details of the interactions between these E6 and E7 proteins and their cellular targets. The final goal of this project is to find a drug lead/hit, which binds tightly to and incapacitates the oncogenic HPV proteins but which do not interact with other cellular proteins.
While the main expertise of my lab is protein engineering and kinetics we also use NMR, X-ray crystallography, single molecule spectroscopy and other techniques, via collaborations with a number of great scientists to whom I am much grateful.
Selected publications
Haq, S. R., Jürgens, M. C., Chi, C. N., Elfström, L., Koh, C. S., Selmer, M., Gianni, S., and Jemth, P. (2010) The plastic energy landscape of protein folding: A triangular folding mechanism with an equilibrium intermediate for a small protein domain. J. Biol. Chem. 285, 18051-18059.
Bach, A., Chi, C. N., Pang, G. F., Olsen, L., Kristensen, A. S., Jemth, P., and Strømgaard, K. (2009) Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95/NMDA receptor interaction. Angew. Chem. Int. Ed. 48, 9685-9689.
Chi, C. N., Bach, A., Engström, Å., Wang, H., Strømgaard, K., Gianni, S., and Jemth, P. (2009) A sequential binding mechanism in a PDZ domain. Biochemistry 48, 7089-7097.
Calosci, N., Chi, C. N., Richter, B., Camilloni, C. Engström, Å., Eklund, L., Travaglini-Allocatelli, C., Gianni, S., Vendruscolo, M. and Jemth, P. (2008) A comparison of the successive transition states for folding reveals alternative early folding pathways. Proc. Natl Acad. Sci. USA. 105, 19241-19246.