The Svedberg Award 2009
Per Hammarström
Assistant professor and group leader at the Department of
Physics, Chemistry and Biology at Linköping University.
A committee consisting of members from the SFBM and Swedish National
Committee for Molecular Biosciences boards has decided to propose
Per Hammarström to the Svedberg Award 2009 for his "Innovative contributions to the understanding of protein misfolding at a
molecular level. His research contributes to understanding diseases caused by
aberrant protein folding and protein aggregation." Hammarström is
affiliated at the Department of Physics, Chemistry and Biology at
Linköping University.
The award of SEK 35 000 together with the medal and diploma will be presented at
the FEBS congress in Göteborg on 26 June-1 July 2010.
Presentation of Hammarström's research
Background
I received my MSc in
Biochemistry at Linköping University in 1995 and joined thereafter Uno
Carlsson´s research group as a PhD student. During my PhD studies I worked on
protein folding studies of the protein carbonic anhydrase. Carbonic anhydrase
was considered a monster in protein folding studies. 259 residues long,
dominated by beta-sheet structure and filled with seventeen proline residues. CA
did not follow simple kinetics and populated several folding intermediates. The
notion at the time was that model proteins for folding studies should be fast
folders i.e. small proteins (>130 residues was deemed large) preferably with
alpha-helical structure stabilized by local contacts and to make circular
dichroism studies easier. Preferably model proteins should be 2-state folders
(only populating the native and unfolded conformation at equilibrium) since
intermediates were considered off-pathway species and merely complicated the
folding reaction. Anyway we worked diligently with CA and made some intriguing
findings. We were interested in studying two specific aspects of protein
folding: i) The interaction with folding assistants, i.e. molecular chaperones,
that prevented protein aggregation, and ii) How residual structure in the
unfolded protein guided folding towards the native state. We used new labeling
methods to study residual structure of the unfolded state and interactions with
the molecular chaperone GroEL.
After my PhD defense I received a Wenner-Gren fellow stipend and I joined Jeff Kelly at The Scripps Research Institute 2000-2002, where I studied the serum protein transthyretin, a protein linked to several amyloid diseases in humans, both sporadic and inherited. On transthyretin we were used biophysical measurements to reveal mechanistic insight into how the native protein was stabilized/destabilized by mutations and small molecule ligands. Ligands that we showed raised the kinetic threshold for TTR dissociation have recently entered clinical studies (now at phase II) for treatment of familial amyloidotic polyneuropathy, showing that biophysical protein folding studies are highly relevant for drug development. After my post-doc I returned to LiU on to a recruitment grant from SSF, and backed by the Wenner-Gren repatriation grant I started my group. I have since then been very fortunate to receive a junior research fellow position from VR and a FFL-2 grant from SSF, and most recently a KVA research fellow position. I was appointed Professor of Protein Chemistry in 2008.
Protein folding is an amazing example of molecular self-organization. With an astronomical number of possible conformations for the unfolded polypeptide the protein will fold spontaneously within fractions of a second (for small proteins) to minutes (for larger proteins).
Protein aggregation was for decades regarded as a mere nuisance in protein research. This process often occurred after a tedious isolation procedure for functional studies and in concentrated protein solutions used for setting up crystallization screens. Just as frustrating were the early days of protein folding when protein samples turned opalescent during rapid dilution of a chemically denatured protein in the stopped flow machine or during thermal denaturation. Few researchers at the time realized that the misfolded states of proteins would hold the key to some of the most severely debilitating diseases known to man.
With the discovery of molecular chaperones in the 1980s and their essentiality in cellular homeostasis things started to change. In the medical community, the discovery of insoluble protein deposits as pathognomonic hallmarks in various human diseases made researchers and pathologists alike realize that there was more to this than mere coincidence. The most amazing quality of protein folding is that it actually works at all, rendering functional proteins from the nascent chain protruding from the ribosome, despite the complex crowded environment of the cell and that the protein can undergo dramatic conformational conversions (folded to unfolded and back) in the surrounding hostile environment of the extracellular space.
Current research
It is today recognized that impaired protein folding
plays a key role in a wide variety of diseases. The misfolding diseases can for
simplicity be divided into three main categories:
1) Loss-of-function diseases (e.g. Marble brain disease)
2) Gain-of-toxic-function diseases (e.g. Alzheimer’s disease)
3) Infectious protein misfolding (e.g. Creutzfeldt-Jakob disease)
There are substantial overlaps between these disease categories and for many diseases it is still not clear which of these mechanisms that are dominant for disease pathology. In several instances it is likely a combination of 1 and 2, which will further drive a vicious cycle of cell stress and organ impairment.
In my research group we are especially interested in how the conformational spaces of misfolded proteins are dictated and which folds/assembly forms that are pathogenic and which are not. We also investigate the effect of molecular chaperones, natural protectors against misfolded proteins, and small molecule ligands on the misfolding processes. In collaboration with others we model amyloid disease in transgenic Drosophila melanogaster and study functional response in vitro (cell culture or human fluids such as plasma).
One of the most intriguing aspects of these diseases is the templated conformational conversion that is believed to be the basis for prion infection. We investigate if this is a common molecular denominator for the amyloidoses, which could render the notion of prion-like infections a possibility in a vast array of more widespread diseases including Alzheimer´s disease. We study the human prion protein, the amyloid beta peptide and transthyretin which are all linked to protein deposition in the form of amyloid in vivo. There is ample evidence that different point mutations in these proteins dictate the disease phenotype. For the human prion protein around 20 different point mutations and two SNPs (rendering single residue substitutions) have been described which all present different disease phenotypes. The same phenomenon holds true for transthyretin (>100 mutations have been identified) and for amyloid beta which also extensively varies in peptide chain length, depending on processing. Our goal is to understand the prerequisites for amyloid fibril formation and conformational stability of both the native structure and the misfolded conformations. We have found that several aggregated forms of proteins can interconvert emphasizing that these are dynamic structures with rather shallow barriers between them. As spin-off effects, our findings could potentially be used for diagnostic and therapeutic intervention in these diseases.
Examples of publications on different proteins linked to misfolding diseases
“Amyloid Fibrils of Human
Prion Protein are Spun and Woven from Morphologically Disordered Aggregates”.
Almstedt K, Nyström S, Nilsson KPR, Hammarström P. Prion (2009), 3 (4),
in press.
“Modeling familial amyloidotic polyneuropathy (Transthyretin V30M) in Drosophila
Melanogaster”. Berg I, Thor, S, Hammarström P. Neurodegener Dis. (2009) 6(3):127-38.
“Small-molecule suppression of misfolding of mutated human carbonic anhydrase II
linked to marble brain disease”. Almstedt K, Rafstedt T, Supuran CT, Carlsson U, Hammarström P. Biochemistry (2009), 48(23):5358-64.
“Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's
disease using novel luminescent probes”. Nilsson KP, Aslund A, Berg I, Nyström S, Konradsson P, Herland A, Inganäs O, Stabo-Eeg F, Lindgren M, Westermark GT, Lannfelt L, Nilsson LN, Hammarström P. ACS Chem Biol. (2007) 2(8):553-60.
“Lysozyme amyloidogenesis is accelerated by specific nicking and fragmentation but
decelerated by intact protein binding and conversion”. Mishra R, Sörgjerd K, Nyström S, Nordigården A, Yu YC, Hammarström P. J Mol Biol. (2007) 23;366(3):1029-44.