Date Thesis Awarded


Access Type

Honors Thesis -- Access Restricted On-Campus Only

Degree Name

Bachelors of Science (BS)




Lizabeth A Allison

Committee Members

Shantá D. Hinton

Diane C. Shakes

Randolph A. Coleman


The thyroid hormone receptor alpha 1 (TRa1) is a member of the nuclear receptor superfamily. TRa1 is a shuttling protein that is primarily localized inside the nucleus, where it serves as a transcription factor. TRa1 mediates transcription upon thyroid hormone (TH) binding and is expressed in numerous tissues that affect cell growth, metabolism, and development. Mutations occurring in TRa1 have been suggested not only to play a role in the disease pathology of cancer but also in the disease known as Resistance to Thyroid Hormone (RTH) syndrome. TRa1 consists of four domains, namely the A/B domain, DNA-binding domain, Hinge domain, and ligand binding domain. Despite what is known on a biochemical level through cell-based assays, the structure of TRa1 is unclear in the conserved DNA-binding domain and Hinge domain and unknown regarding the A/B domain. The purpose of this thesis was to ascertain the localization patterns of specific RTH mutants, namely A263S and N359Y, and understand the intricate residue-residue interactions that cause mutant TRa1 to aberrantly localize in cells. Through the use of biochemical assays and computational methods, including protein prediction modeling and molecular dynamics (MD) simulations, residue-residue networks were determined for TRa1 mutants. Likewise, a novel selectivity filter was discovered in two regions of TRa1 that is prone to cause aggregation in mutant TRa1. The implication of this latter discovery is the targeting of these sites with small molecule inhibitors in hopes of rescuing the formation of aggregates seen in cells, which may contribute to the disease pathogenesis.

On-Campus Access Only