The Role of Force-Sensitive Interactions in Amyloid Assembly by Fungal Adhesins
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Authors
Petkovic, Andrea
Date
2025-01-30
Type
thesis
Language
eng
Keyword
Adhesin , Fungal Adhesin , Candida albicans , Als adhesin , Force-sensitive , Amyloid , Biofilm
Alternative Title
Abstract
Candida albicans is a common human fungal pathogen that forms stubborn biofilms on host tissues and implanted cosmetic and medical devices such as contact lenses, dentures, catheters, and joint prostheses. These biofilms assemble through cooperative cell-to-cell attachments using surface-localized adhesin proteins. Some adhesins also help maintain biofilm integrity by forming fibrous protein aggregates that are linked together by non-covalent bonds between a hydrophobic segment of their sequence, termed the amyloid-forming region (AFR). At the core of these adhesin aggregates are parallel or anti-parallel β-sheet arrays, which can layer onto other adhesin β-sheets by sidechain–sidechain interactions to form highly stable amyloid fibrils. The Als (agglutinin-like sequence) proteins are one type of the amyloid fibril-forming adhesin that decorates the cell wall of C. albicans and have been implicated in pathogenesis and biofilm formation. Though some efforts have succeeded in modeling the structures of Als adhesins before and after amyloid formation, little is known about the mechanism of this structural transition. It appears that their AFR is concealed by the bordering N-terminal and T domains prior to amyloid assembly, and shear force-induced partial unfolding of the Als protein is required to expose its AFR, allowing amyloid formation to proceed. We investigated this putative mechanism by examining the relationship between the stability of AFR-concealing intramolecular interactions in the Als5 adhesin and the amount of shear force needed to trigger amyloid formation. Our approach involved developing a surrogate cell system to host and test this relationship for individual Als proteins that had been site-specifically altered to either restrict or facilitate exposure of their AFR under varying levels of shear force. These studies helped identify a shear force-responsive bond near the AFR that appears to aid in AFR concealment.
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Attribution-NonCommercial-NoDerivatives 4.0 International
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivatives 4.0 International