Taurine is a functional regulator of transthyretin; implication in transthyretin-induced hypothyroidism and amyloidosis

Abstract

Transthyretin (TTR) is a homo-tetrameric, 55 kDa, transport protein synthesized mainly in the liver, retinal epithelium, choroid plexus, placental villi and uterus. The main function of TTR is transport of thyroxine (T 4 ) and retinol-binding protein, while it also plays a crucial role in neuroprotection. The binding of thyroxine assists in maintaining the stability of the native tetramer, which is crucial for its functionality. Eventually, dissociation of the tetramer to its monomer results in the formation of toxic oligomeric TTR species and their deposition causes diseases such as cardiomyopathy, polyneuropathy, dementia and preeclampsia. While current kinetic stabilizers occupy the hydrophobic thyroxine-binding pocket, identifying endogenous modulators that maintain TTR homeostasis without impairing hormone transport remains a key objective. In this study, we investigated taurine—a vital neuronal osmolyte and endogenous chemical chaperone—as a functional regulator of TTR dynamics. In the present study, we have systematically evaluated the effect of taurine on the structure-function paradigm of TTR using various biochemical, biophysical tools and cellular model. We discovered that taurine exhibits preferential binding to TTR leading to functional enhancement of T 4 -binding affinity and exhibits anti-aggregation potential towards TTR amyloidosis. Further examination of the mechanism revealed that taurine exhibits preferential binding to TTR microstates and restricts local conformational fluctuations, without altering the global native structure or thermodynamic folding. Together, these findings identify taurine as a trans-acting allosteric chemical chaperone of TTR. This discovery of functional regulation of TTR by taurine offers a promising, non-toxic therapeutic strategy in repurposing of taurine (an FDA-approved supplement) for TTR amyloidosis and TTR-induced hypothyroidism, especially in neuronal and gestational impairments.