Astrid Gräslund

Research program:
Spectroscopic studies of structure, dynamics and reactions of biological macromolecules.
 

Address:
E-mail: astrid.graslund@dbb.su.se 
Phone: (+46)-8-16 2450 
Fax: (+46)-8-155597

Research group and coworkers:
Axel Abelein, Torbjörn Astlind, Johannes Björnerås, Göran Eriksson, Fatemeh Madani, Britt-Marie Olsson, Ana Popovic-Bijelic,  Anna Wahlström

Project description:
Our research program has two parts: ribonucleotide reductase and bioactive peptides, including their membrane interactions. The aim is to relate structure, dynamics, and interactions studied by spectroscopy to the biological reactions and functions. Our methods are high resolution NMR, EPR, and optical spectroscopy including CD and fluorescence.

Ribonucleotide reductase
Ribonucleotide reductase (RNR) converts ribonucleotides to deoxyribonucleotides. Its activity is required for DNA synthesis and repair. One of the two components of class I RNR of higher organisms or E. coli, protein R2, contains a diferric iron site and a neighbouring free radical on a tyrosyl residue. Between the active site in the R1 component and the radical site in R2 there exists a conserved chain of H-bonded amino acids, involved in long range coupled electron/proton transfer. The aim of our EPR work on RNR is to learn more about (a) the intriguing properties of class I RNR from the Chlamydia bacterium where the role of the tyrosyl radical is replaced by an oxidized form of a mixed manganese-iron cluster, and (b) another group of enzymes (in bacteria) with a similar manganese-iron cluster at the active site, but with a different function, probably as oxygenases or oxidases.

Bioactive peptides
Peptides, their structures, dynamics and interactions with biomembranes is our second project part, where high-resolution NMR is the main method. The Alzheimer Ab (1-39 up to 43) peptide is the major constituent of the senile plaques found in the brains of Alzheimer patients. The precipitating peptides causing disease is an example of a larger class of phenomena, protein aggregation diseases, to which also e.g. spongiform encephalopathies (Creuzfeldt-Jakob) belong. The process of protein aggregation concomitant with secondary structure conversion to b-sheet, followed by precipitation and fibril ("amyloid") formation is a common phenomenon in these cases. The aim of our work is to understand the details of the molecular interactions that lead to aggregation and secondary structure conversion of the Alzheimer peptide. This work includes interactions with metal ions, as well as with small molecules that modify the aggregation processes. Another project part deals with Cell Penetrating Peptides (CPPs), which have been shown to traverse biological membranes and deliver large protein cargoes inside the cell. Our studies aim at understanding the molecular mechanism(s) of membrane translocation for these peptides. We also study the dynorphin neuropeptides and peptides derived from prion proteins, in both cases with interesting membrane interactions which may be related to biological functions.

Selected recent publications

Löfgren, K., Wahlström, A., Lundberg, P., Langel, U., Gräslund, A. and Bedecs, K. Anti-prion properties of prion protein-derived cell-penetrating peptides. FASEB J. 22 (2008) 2177-2184.

Wahlström, A., Hugonin, L., Peralvarez-Marin, A., Jarvet, J. and Gräslund, A. Secondary structure conversions of Alzheimer´s Ab(1-40) peptide induced by membrane-mimicking detergents. FEBS J. 275 (2008) 5117-5128

Hugonin, L., Barth, A., Gräslund, A. and Peralvarez-Marin, A. Secondary structure transitions and aggregation induced in dynorphin neuropeptides by the detergent sodium dodecyl sulfate. Biochim. Biophys. Acta 1778 (2008) 2580-2587.

Voevodskaya, N., Lendzian, F., Sanganas, O., Grundmeier, A, Gräslund, A. and Haumann, M. Redox intermediates of the Mn-Fe site in the subunit R2 of Chlamydia trachomatis ribonucleotide reductase: An X-ray absorption and EPR study. J. Biol. Chem. 284 (2009) 4555-4566.

Madani, F., Lind, J., Damberg, P., Adams, S.R., Tsien, R.Y. and Gräslund, A. Hairpin structure of a biarsenical-tetracysteine motif determined by NMR spectroscopy. J. Am. Chem. Soc. 131 (2009) 4613-4615.

Popovic-Bijelic, A., Voevodskaya, N., Domkin, V., Thelander, L. and Gräslund, A. Metal binding and activity of protein R2 mutants: conditions for formation of the mixed manganese-iron cofactor. Biochemistry, 48 (2009) 6532-6539.

Guterstam, P., Madani, F., Hirose, H., Takeuchi, T., Futaki, S., El Andaloussi, S., Gräslund, A. and Langel, Ü. Elucidating cell-penetrating peptide mechanisms of action for membrane interaction, cellular uptake and translocation, utilizing the hydrophobic counter-anion pyrenebutyrate. Biochim. Biophys. Acta 1788 (2009) 2509-2517.

Zhang, X., Oglecka, K., Sandgren, S., Belting, M., Esbjörner-Winters, E., Norden, B. and Gräslund, A. Dual functions of the human antimicrobial peptide LL-37 – Target membrane perturbation and host cell cargo delivery. Biochim. Biophys. Acta 1798 (2010) 2201-2208.

Lendel, C., Bolognesi, B., Wahlstrom, A., Dobson, C. and Gräslund, A. Detergent-like interaction of congo red with the amyloid bpeptide. Biochemistry 49 (2010) 1358-1360.

Lindgren, J., Wahlström, A., Danielsson, J., Markova, N., Ekblad, C., Gräslund, A., Abrahamsén, L., Eriksson Karlström, A., and Wärmländer, S. N-terminal engineering of amyloid-beta-binding Affibody molecules yeilds improved chemical synthesis and higher binding affinity. Protein Sci. 19 (2010) 2319-2329.

List of publications via PubMed

Curriculum vitae
 

Acknowledgements
These studies are supported by grants from the Swedish Science Council,  the Swedish Foundation for Strategic Research, and the Swedish Brain Foundation