Exploring the Influence of Mutation on Transthyretin Aggregation in Heart Disease

Author(s): Ankita Sharma, Monu, Sagarika Biswas*

Journal Name: Current Computer-Aided Drug Design

Volume 14 , Issue 2 , 2018

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Graphical Abstract:


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.

Keywords: CAD, DUET, Folding RaCe, I-Mutant, SNAP2, MuPro, SDM, Polyphen2.

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Article Details

Year: 2018
Page: [125 - 130]
Pages: 6
DOI: 10.2174/1573409914666180321104749
Price: $65

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