Understanding how a polypeptide chain achieves its native fold and the complex interplay between folding and aggregation remains, even after over 40 years, an area of active research. Particularly, understanding how large, topologically complex proteins fold and avoid aggregation is crucial for the advancement of the field. This thesis specifically investigates the relationship between folding and aggregation of large, β-sheet rich proteins with complex folding mechanisms with an emphasis on β-helical proteins such as pertactin. While β-sheet rich proteins tend to have slower folding kinetics and increased population of aggregation prone intermediates (1, 2), β-sheet rich proteins can avoid aggregation and robustly fold (3). Specifically, β-helical proteins possess structural caps that prevent aggregation that can be identified by our structure-based prediction program, HELIXCAP (4). Additionally, aggregation is often viewed as an irreversible fate for folding polypeptides, yet as demonstrated by this work, it can be a dynamic process. During refolding, pertactin forms loose, unstructured transient insoluble aggregates (TIA) that disassemble without the aid of molecular chaperones to productively fold to the native state. Understanding how proteins assemble into aggregate structures, such as the unstructured TIA or the large rope-like fibril aggregates (5) described in this thesis, can lead to controlled assembly for biomaterials applications and/or prevention of unwanted aggregation.
|Author||Jennifer Laura Starner-Kreinbrink|
|Contributor||Brian Baker, Committee Member|
|Contributor||Anthony Serianni, Committee Member|
|Contributor||Shahriar Mobashery, Committee Member|
|Degree Level||Doctoral Dissertation|
|Degree Discipline||Chemistry and Biochemistry|
|Departments and Units|