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Kinetic mechanisms of protein misfolding and amyloid plaque formation

Applicant Kiefhaber Thomas
Number 50278
Funding scheme NRP 38 Diseases of the Nervous System
Research institution Abteilung Biophysikalische Chemie Biozentrum der Universität Basel
Institution of higher education University of Basel - BS
Main discipline Biochemistry
Start/End 01.06.1997 - 31.05.2000
Approved amount 366'672.00
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Keywords (5)

PROTEIN MISFOLDING; AMYLOID PLAQUES; PROTEIN STRUCTURE; PROTEIN AGGREGATION; POLYMERIZATION KINETICS

Lay Summary (English)

Lead
Lay summary
We investigated the molecular mechanism of protein misfolding and amyloid plaque formation using the small all-beta sheet protein tendamistat. Folding and unfolding of tendamistat is highly co-operative and reversible. We found that some destabilized mutant forms of the protein are able to form an alternatively folded conformation in addition to the native state. This conformation is self-associating to soluble multimers of 40 monomer units. These are slowly aggregating to amyloid fibrils. Structural rearrangements in a beta-hairpin of the protein are essential for amyloid formation. Kinetic measurements suggest a dimerization process with subsequent multiple binding steps as molecular mechanism for formation of the soluble oligomer. We did not see any evidence for an autocatalytic stept in this process. The oligomeric state seems to be an essential intermediate in amyloid fibril formation. Efforts to induce amyloid formation in soluble variants of tendamistat in the presence of pre-formed fibrils failed, suggesting structural flexibility induced by the mutations to be essential for fibril formation.
Direct link to Lay Summary Last update: 21.02.2013

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