Intrinsically Disordered Protein Regions in Human Evolution and as Therapeutic Targets

Author

Karen Paco MendivilFollow

Date Degree Awarded

Fall 12-16-2021

Degree Type

Open Access Dissertation

Degree Name

PHD in Applied Life Sciences

First Thesis/Dissertation Advisor

Larry Grill

Second Thesis/Dissertation Advisor

Animesh Ray

Third Thesis/Dissertation Advisor

Rachita Sumbria

Terms of Use & License Information

Terms of Use for work posted in Scholarship@Claremont.

Abstract

Intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) fail to form stable structures but have important biological functions via interacting with various molecular partners (proteins, DNA, RNA, glycosaminoglycans). We hypothesized that IDPRs are potential targets for therapeutics development because they are reservoirs of evolutionary innovation, and they play crucial roles in adaptation to pathogens.

We first studied the evolution of IDPRs in the human proteome and compared it with the proteome of non-human primates. We have found that evolutionary young protein-coding genes have included low conserved regions in the N-terminal part of proteins, and such regions are linked to high disorder scores. Although humans share high genomic similarities with their closest relatives such as chimpanzees and other non-human primates, we are more susceptible to diseases. It has been shown that humans respond differently to infectious diseases when compared to primates, the study of structural differences in evolutionary young human proteins could potentially help to discover new therapeutic targets that are linked to human-specific pathologies.

In addition, we propose that disordered regions are important targets in vaccine development. Pathogens incorporate disordered regions on their proteomes to interact more efficiently with their host. We chose several IDPRs of the spike protein of the SARS CoV-2 virus to demonstrate in vivo that these regions are antigenic. Our Chimeric Qβ virus-like particles displaying disordered segments of SARS CoV-2 spike protein-induced robust antibody responses in BALB/c mice. We demonstrate evidence that IDPRs can be efficient epitopes for the development of efficacious vaccines.

Rights Information

© 2022 Karen Y Paco Mendivil

Recommended Citation

Paco Mendivil, Karen. (2021). Intrinsically Disordered Protein Regions in Human Evolution and as Therapeutic Targets. KGI Theses and Dissertations, 26. https://scholarship.claremont.edu/kgi__theses/26.