Insights to Protein Pathogenicity from the Lens of Protein Evolution

Authors

Janelle Nunez-CastillaFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biology

First Advisor's Name

Jessica Siltberg-Liberles

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Prem Chapagain

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Timothy Collins

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Matthew DeGennaro

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Wensong Wu

Fifth Advisor's Committee Title

Committee member

Keywords

intrinsically disordered proteins, p53, functional divergence, flaviviruses, Zika virus, antiviral drug targets, coronaviruses, molecular mimicry, epitopedia, COVID-19

Date of Defense

6-29-2022

Abstract

As protein sequences evolve, differences in selective constraints may lead to outcomes ranging from sequence conservation to structural and functional divergence. Evolutionary protein family analysis can illuminate which protein regions are likely to diverge or remain conserved in sequence, structure, and function. Moreover, nonsynonymous mutations in pathogens may result in the emergence of protein regions that affect the behavior of pathogenic proteins within a host and host response. I aimed to gain insight on pathogenic proteins from cancer and viruses using an evolutionary perspective. First, I examined p53, a conformationally flexible, multifunctional protein mutated in ~50% of human cancers. Multifunctional proteins may experience rapid sequence divergence given trade-offs between functions, while proteins with important functions may be more constrained. How, then, does a protein like p53 evolve? I assessed the evolutionary dynamics of structural and regulatory properties in the p53 family, revealing paralog-specific patterns of functional divergence. I also studied flaviviruses, like Dengue and Zika virus, whose conformational flexibility contributes to antibody-dependent enhancement (ADE). ADE has long complicated vaccine development for these viruses, making antiviral drug development an attractive alternative. I identified fitness-critical sites conserved in sequence and structure in the proteome of flaviviruses with the potential to act as broadly neutralizing antiviral drug target sites. I later developed Epitopedia, a computational method for epitope-based prediction of molecular mimicry. Molecular mimicry occurs when regions of antigenic proteins resemble protein regions from the host or other pathogens, leading to antibody cross-reactivity at these sites which can result in autoimmunity or have a protective effect. I applied Epitopedia to the antigenic Spike protein from SARS-CoV-2, the causative agent of COVID-19. Molecular mimicry may explain the varied symptoms and outcomes seen in COVID-19 patients. I found instances of molecular mimicry in Spike associated with COVID-19-related blood-clotting disorders and cardiac disease, with implications on disease treatment and vaccine design.

Identifier

FIDC010788

ORCID

0000-0002-3608-4512

Comments

For Chapter 2, Janelle Nunez-Castilla and Helena Gomes Dos Santos are co-first authors

For Chapter 4, Janelle Nunez-Castilla and Christian Balbin are co-first authors

Previously Published In

Dos Santos, H.G., Nunez-Castilla, J., and Siltberg-Liberles, J. (2016). Functional diversification after gene duplication: paralog specific regions of structural disorder and phosphorylation in p53, p63, and p73. PLoS ONE, 11(3), e0151961. https://doi.org/10.1371/journal.pone.0151961

Nunez-Castilla J., Rahaman, J., Ahrens, J.B., Balbin, C.A., and Siltberg-Liberles, J. (2020). Exploring evolutionary constraints in the proteomes of Zika, Dengue, and other Flaviviruses to find fitness-critical sites. Journal of Molecular Evolution, 88(4), 399-414. https://doi.org/10.1007/s00239-020-09941-5

Nunez-Castilla, J., Stebliankin, V., Baral, P., Balbin, C. A., Sobhan, M., Cickovski, T., Mondal, A. M., Narasimhan, G., Chapagain, P., Mathee, K., and Siltberg-Liberles, J. (2022) Potential autoimmunity resulting from molecular mimicry between SARS-CoV-2 Spike and human proteins. Viruses, 14(7): 1415. https://doi.org/10.3390/v14071415

Recommended Citation

Nunez-Castilla, Janelle, "Insights to Protein Pathogenicity from the Lens of Protein Evolution" (2022). FIU Electronic Theses and Dissertations. 5035.
https://digitalcommons.fiu.edu/etd/5035