Towards an understanding of ß-sheet folding and misfolding

• Applicant: Dr. Marcus Jäger
• Subject Area: Biochemistry
• Term: from 2000 to 2002
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5256708

A small antiparallel ß-sheet protein, the WW-domain, will be studied by rapid kinetics with sub-µs time resolution, to understand whether turns or hydrophobic clusters or a combination thereof are the rate determining step(s) in ß-sheet formation. The project combines synthetic organic chemistry, protein chemistry, and physical chemistry and is focused on understanding the structural features of transition states(s) associated with ß-sheet folding - a poorly understood area of current interest. The project is important because kinetic paritioning between states determines wheter proper ß-sheet folding or neurodegenerate misfolding (amyloid fibril formation) occurs. There is a ongoing debate in the literature as to whether the formation of ß-turns or hydrophobic clusters are rate limiting in ß-sheet folding. The WW-domain is well suited to carry out the kinetic experiments needed to resolve this debate. Knowledge from this research will allow us to understand ß-sheet folding in more detail critical to our understanding of the second half of the genetic code. A signifcant question when considering relevance issues; how can we understand ß-sheet misfolding associated with Huntington/Alzheimers disease if we cannont appreciate the details of the normal ß-sheet folding process.

• DFG Programme: Research Fellowships
• International Connection: USA