Dissertation committee:
Σταύρος Ι. Χαμόδρακας Ομοτ. Καθηγητής (Επιβλέπων), Κωνσταντίνος Βοργιάς Καθηγητής, Βασιλική Οικονομίδου Επίκ. Καθηγήτρια
Summary:
Amyloid fibrils are formed by soluble proteins/peptides that convert under
certain denaturing conditions into insoluble fibrous aggregates. Several
proteins with important but otherwise unrelated functions have been associated
with amyloid deposition, although they present neither sequence nor structural
similarities. A number of widespread diseases, such as AL, AA or ATTR
amyloidosis, neurodegenerative diseases (Alzheimer’s, Parkinson’s or
Creutzfeldt-Jakob’s disease), type-II diabetes and several other major
pathological conditions are a consequence of unrestrained deposition of amyloid
causing tissue degeneration. However, organisms spanning from bacteria to
humans occasionally produce functional amyloids, in an effort to support
pivotal biological processes. Structural studies reveal that short sequence
stretches with high aggregation propensity promote the overall amyloidogenic
tendency of a protein. Such “aggregation-prone” regions, named amyloidogenic
determinants, are responsible for the self-aggregation of proteins associated
with the formation of amyloids. This thesis was focused towards the
identification and experimental verification of “aggregation-prone” segments in
amyloidogenic proteins associated with the formation of both functional and
pathological amyloids. An integrative structural/biophysical approach was
carried out, utilizing transmission electron microscopy, X-ray diffraction, ATR
FT-IR spectroscopy and polarizing microscopy. Furthermore, computational
studies were performed utilizing several bioinformatics techniques. The above
were combined in an effort to uncover the unknown underlying mechanisms behind
the formation and structure of amyloid fibrils.
Keywords:
Amyloid fibrils, Functional Amyloids, Protein Aggregation, Molecular Modeling, Aggregation-prone segments