Further Analysis of RTHα(N359Y)

In the previous post, I addressed the ab initio folding of thyroid hormone receptor alpha and its mutant variance, RTHα through a in silico protein folding program. Today, I address the potential interactions and stability of this receptors. The fundamental challenge of of protein analysis is the complexity of its residue-residue interactions. Since the protein structure is not fully resolved, except for the Ligand Binding Domain, the initial problem was figuring out a method by which its primary sequences could be folded. This issue was resolved through an ab initio folding of the protein, which means that the folding is not dependent on the homology structures. Therefore, this type of folding does not require the use of homology structures. In a past paper addressing the stability of the Aldose Reductase, Balendiran et al utilized the B-Factor parameter to analyze the relative stability selected domains. Using this method, I grouped the amino acid sequence according to each domain and analyzed the relative stability of each domain.

[Read more…]

Protein Modeling of Wild-type TRs and RTH mutants

To understand and explain localization of thyroid hormone receptors, I performed an ab initio folding of the primary sequences for both the wild-type and the mutant receptors. The mutant receptor demonstrated a potential conformational change. Therefore, I overlapped the two receptors together and create a predicted model how the wild-type receptor would conformationally shift to the mutant. The conformational change occurs within the DNA-Binding Domain, which could potentially affect the binding affinity between the receptor and the thyroid response elements. The following is selected times within the animation, which should the progressive conformational changes within the DBD.

[Read more…]

hTRa1 RTH Abstract

Thyroid hormone receptors (TRs) contain nuclear localization signals (NLSs) and nuclear export signals (NESs), which allow them to undergo nucleocytoplasmic shuttling. Mutations in TRs have been associated with Resistance to Thyroid Hormone Syndrome (RTH). This proposal examines two separate mutations in the THRA gene, which encodes a major subtype of TR, called TRa1, that causes RTHa. These mutations were found in two patients who exhibited hypothyroidism and hypercalcemia with severe bone malformations. One mutation leads to an amino acid change from alanine to serine at position 263 (A263S) in TRa1, and the other mutation changes asparagine to tyrosine at position 359 (N359Y). Both amino acid substitutions are located near known NESs in TRa1. I will characterize how these amino acid mutations influence the intracellular localization of TRa1, and use structural models to understand structure-function relationships.

[Read more…]