Background: Transthyretin (TTR) is the transporter protein (55 kDa) that carries retinolbinding
protein and Thyroxin (T4) in its functional tetramer form. Presence of the mutation in this protein
(TTR) may lead to the dissociation of tetramers to monomer which unfolds and self-associates to
form amyloid aggregates. Aggregation of this protein has been found to be associated with various lifethreatening
disorders such as Coronary Artery Disease (CAD) which is the major cause of mortality
and morbidity worldwide.
Methods: In the present communication, we have predicted mutation prone residues of TTR with the
help of suspect server. Substitution (T139R with 95 score) occurring at the thyroid hormone binding
site was selected for studying the mutational consequences on TTR. The effect of mutation on stability,
functionality, aggregation and folding rate was analyzed by MuPro, DUET, SDM, SNAP2, Polyphen2,
PASTA2.0, Aggrescan and Folding RaCe servers. The presence of TTR monomer in CAD plasma has
been observed through Western blot analysis.
Results: T139R mutation may expose the buried regions of TTR protein which help in the self
association and the increase in the stability may help in the TTR deposition. Structural analysis indicated
that F and H strands of TTR are more prone to aggregation. Thus, T139R mutation might cause
these residues to be aggregation prone and change in folding rate and validated TTR monomer in diseased
cases by Western blot analysis.
Conclusion: The observed results clearly indicated that the occurrence of this mutation is causing the
impact on the structural and functional significance of TTR by interfering in the formation of tetramer.
Thus, hindrance created to thyroxin transportation resulted in higher lipid levels in the blood that ultimately
might promote the progression of the CAD.