8HY4

Crystal structure of human transthyretin variant A97S at pH 7.6

Summary for 8HY4

• Entry DOI: 10.2210/pdb8hy4/pdb
• Descriptor: Transthyretin (2 entities in total)
• Functional Keywords: transport thyroxine, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29991.42

Authors

Wang, Y.S.,Huang, C.H.,Tzeng, S.R. (deposition date: 2023-01-05, release date: 2023-05-03, Last modification date: 2024-05-29)

Primary citation

Wang, Y.S.,Huang, C.H.,Liou, G.G.,Hsueh, H.W.,Liang, C.T.,Tseng, H.C.,Huang, S.J.,Chao, C.C.,Hsieh, S.T.,Tzeng, S.R.
A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser.
Protein Sci., 32:e4610-e4610, 2023

PubMed Abstract: Transthyretin (TTR)-related amyloidosis (ATTR) is a syndrome of diseases characterized by the extracellular deposition of fibrillar materials containing TTR variants. Ala97Ser (A97S) is the major mutation reported in Taiwanese ATTR patients. Here, we combine atomic resolution structural information together with the biochemical data to demonstrate that substitution of polar Ser for a small hydrophobic side chain of Ala at residue 97 of TTR largely influences the local packing density of the FG-loop, thus leading to the conformational instability of native tetramer, the increased monomeric species, and thus the enhanced amyloidogenicity of apo-A97S. Based on calorimetric studies, the tetramer destabilization of A97S can be substantially altered by interacting with native stabilizers via similarly energetic patterns compared to that of wild-type (WT) TTR; however, stabilizer binding partially rearranges the networks of hydrogen bonding in TTR variants while FG-loops of tetrameric A97S still remain relatively flexible. Moreover, TTR in complexed with holo-retinol binding protein 4 is slightly influenced by the structural and dynamic changes of FG-loop caused by A97S substitution with an approximately five-fold difference in binding affinity. Collectively, our findings suggest that the amyloidogenic A97S mutation destabilizes TTR by increasing the flexibility of the FG-loop in the monomer, thus modulating the rate of amyloid fibrillization.

PubMed: 36851846
DOI: 10.1002/pro.4610

Experimental method

X-RAY DIFFRACTION (1.53 Å)