Function
Transthyretin (TTR) is a serum carrier of the thyroid hormone thyroxine (T4) and retinol through its association with retinol-binding protein (RBP). Many small molecules bind to TTR T4-binding site[1], specifically through hydrogen bonding interactions. For details see Tafamidis and Student Project 2 for UMass Chemistry 423 Spring 2015.
Disease
TTR mutations such as V30M[2] are associated with amyloid deposition[3]. Amyloids form when the protein misfolds and forms aggregates called plaques. This can happen via genetic mutation or aging. The plaques can cause neuropathy, heart failure and swelling. Tafamidis is a medication which stabilises TTR and is used in treatment of TTR amyloidosis[4]. An RNAi based treatment has also been approved by the FDA.[5].
Structural highlights
The hormone tyrosine is bound in the active site of TTR[6].
3D structures of transthyretin
Transthyretin 3D structures
- ↑ Robbins J. Transthyretin from discovery to now. Clin Chem Lab Med. 2002 Dec;40(12):1183-90. PMID:12553418 doi:https://dx.doi.org/10.1515/CCLM.2002.208
- ↑ Saraiva MJ, Birken S, Costa PP, Goodman DS. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest. 1984 Jul;74(1):104-19. PMID:6736244 doi:10.1172/JCI111390
- ↑ Saraiva MJ. Transthyretin mutations in health and disease. Hum Mutat. 1995;5(3):191-6. PMID:7599630 doi:https://dx.doi.org/10.1002/humu.1380050302
- ↑ Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. PMID:30145929 doi:10.1056/NEJMoa1805689
- ↑ . FDA approves Alnylam's anti-amyloid RNAi drug for cardiomyopathy. Nat Biotechnol. 2025 Apr;43(4):457. PMID:40229375 doi:10.1038/s41587-025-02656-2
- ↑ Wojtczak A, Luft J, Cody V. Mechanism of molecular recognition. Structural aspects of 3,3'-diiodo-L-thyronine binding to human serum transthyretin. J Biol Chem. 1992 Jan 5;267(1):353-7. PMID:1730601
