The ABCF gene family facilitates aggregate processing
Creators: name: Skuodas, Sydney
Publisher: name: University of Iowa
Year: 2023
Subjects: Abcf2
Aggregation
Amyloid
Arb1
Chaperone
Disaggregase
public abstract

description: Cells devote many resources to maintaining proteostasis, which is the balance between protein synthesis, folding, aggregation/disaggregation, and degradation pathways. A complex network of molecular chaperones ensures the integrity of proteins within a cell by promoting proper folding and preventing uncontrolled aggregation. Disaggregases are a class of chaperones that resolve these protein aggregates to promote cell survival.
description: Amyloids are one type of protein aggregate typical of proteins that can undergo a conformational change from the native, soluble form to a stable cross-β structure. Such amyloid-prone proteins are notorious for their role in human diseases including Huntington’s, Alzheimer’s, and Parkinson’s. In contrast, recent studies have shown that the amyloid conformation can also be associated with physiological functions such as the response to metabolic stress in S. cerevisiae, persistence of memory in D. melanogaster, storage of peptide hormones in mammals, and early animal development. Many possible roles for amyloid have yet to be elucidated. This is especially true of amyloids in development, as amyloids have most often been characterized in adult animal organisms.
description: The regulation of physiological amyloids is important for preventing uncontrolled aggregation, which would inhibit the normal biological function of the amyloid and potentially lead to disease. How are amyloids regulated in animal development? Enzymatic disaggregation is one possible mechanism. The HSP104 gene encoding a potent amyloid disaggregase, HSP104, is present in all genomes except animals. HSP104 encodes a potent and indiscriminate disaggregase which may be incompatible with animal development.
description: We searched for candidate disaggregases which could have a role in amyloid processing during development and identified the ABCF gene family. Knockdown of ABCFs in animals results in developmental defects along with a change in the amyloid phenotypes of early developing animals. To characterize potential disaggregation activities of Abcf proteins, I examined their activities in the genetic model organism, S. cerevisae. My approach included investigating the roles of Arb1 (Abcf2) and Gcn20 (Abcf3) in disordered and ordered aggregate processing utilizing well studied exogenous reporters as well as well-characterized endogenous yeast amyloids, and testing Abcf proteins for potential enzymatic disaggregase activity using model protein aggregates in vitro.
description: I found that yeast Arb1 is essential for the efficient processing of disordered heat-denatured protein aggregates. Arb1 and Gcn20 were also necessary for wild type levels of ordered amyloid aggregation. I also found that Arb1 plays a role in endogenous yeast amyloid processing. Arb1 colocalizes with the disordered and endogenous amyloid reporters, suggesting a possible physical interaction which would be essential for a disaggregase and its protein clients. I determined that animal Abcf proteins also have aggregate processing roles when expressed in yeast. Results of my studies in conjunction with work by collaborators in the Weeks and Phillips laboratories in animals support the role of Abcf proteins in amyloid processing during animal development.