Investigating beta-sheet folding and aggregation

Doctoral Dissertation


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.


Attribute NameValues
  • etd-04172015-154352

Author Jennifer Laura Starner-Kreinbrink
Advisor Brian Baker
Contributor Brian Baker, Committee Member
Contributor Anthony Serianni, Committee Member
Contributor Shahriar Mobashery, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Chemistry and Biochemistry
Degree Name PhD
Defense Date
  • 2015-04-02

Submission Date 2015-04-17
  • United States of America

  • cap structures

  • pertactin

  • beta-sheet

  • protein aggregation

  • protein folding

  • ropes

  • biomaterials

  • University of Notre Dame

  • English

Record Visibility Public
Content License
  • All rights reserved

Departments and Units


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