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Sequence determinants of short stretch protein aggregation

Wednesday, 22 August, 2012 - 16:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculty: Science and Bio-engineering Sciences
Jacinte Beerten
phd defence

The study of protein aggregation has become a dynamic scientific field due to its
correlation with conformational diseases as well as the problems it can cause
during recombinant protein production. Despite decades of research, we still
lack full understanding of the mechanism of protein aggregation.
In this dissertation we have employed a combination of biophysical and
molecular biological approaches to investigate several features and
determinants of protein aggregation.
This work is based upon the short stretch hypothesis, where specific segments of
a polypeptide chain assemble into an intermolecular beta]sheet, thereby
nucleating protein aggregation.

In the first part of this dissertation the sequential determinants of amyloid
formation is investigated by selecting 744 hexapeptides derived from proteins
from several kingdoms of life and classifying them by means of biophysical
techniques into amylogenic or non]amylogenic hexapeptides.
The data obtained in this study together with an additional 453 hexapeptides
from a profound literature study are used to generate an improved Waltz
algorithm that outperforms its competitors in prediction the amyloid forming
capacities of proteins and polypeptides. A first version of the new Waltz
predictor does not show a specific profile for amyloid formation, but instead it
shows an amino acid specificity. Although amyloids are believed to have similar
morphology, our data tend to confirm the existence of several amyloid

In the second part of this dissertation the selective strategy of gatekeeper
residues (arginine, lysine, glutamate, aspartate and proline) at the flanks of an
aggregation prone segment from the E.coli protein RNA polymerase factor
Sigma32 fused to GFP is investigated. Here we show that gatekeeper residues
affect bacterial fitness not only by modulating the intrinsic aggregation
propensity of proteins but also the manner in which they affect the processing of
Sigma32]GFP by the protein quality control system.