7WL6

Crystal structure of I73L mutated human transthyretin

Summary for 7WL6

• Entry DOI: 10.2210/pdb7wl6/pdb
• Descriptor: Transthyretin, MAGNESIUM ION (3 entities in total)
• Functional Keywords: ttr, transthyretin, human, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29928.03

Authors

Nakagawa, M.,Obita, T.,Mizuguchi, M. (deposition date: 2022-01-12, release date: 2022-11-23, Last modification date: 2023-11-29)

Primary citation

Nakagawa, M.,Obita, T.,Mizuguchi, M.
The hydrophobic residue Leu73 is crucial for the high stability and low aggregation properties of murine transthyretin.
Biochem.J., 479:1999-2011, 2022

PubMed Abstract: Destabilization of human transthyretin leads to its aggregation into amyloid fibrils, which causes a rare, progressive and fatal systemic disorder called ATTR amyloidosis. By contrast, murine transthyretin is known to be very stable and therefore does not aggregate into amyloid fibrils in vivo or in vitro. We examined the hydrophobic residues responsible for the high-stability and low-aggregation properties of murine transthyretin using site-directed mutagenesis. Urea-induced unfolding and thioflavin T fluorescence aggregation assay revealed that Leu73 of murine transthyretin largely contributes to its high stability and low aggregation properties: the I73L mutation stabilized human transthyretin, while the L73I mutation destabilized murine transthyretin. In addition, the I26V/I73L mutation stabilized the amyloidogenic V30M mutant of human transthyretin to the same degree as the suppressor mutation T119M, which protects transthyretin against amyloid fibril aggregation. The I73L mutation resulted in no significant differences in the overall structure of the transthyretin tetramer or the contacts of side-chains in the hydrophobic core of the monomer. We also found that Leu73 of murine transthyretin is conserved in many mammals, while Ile73 of human transthyretin is conserved in monkeys and cats. These studies will provide new insights into the stability and aggregation properties of transthyretin from various mammals.

PubMed: 36098398
DOI: 10.1042/BCJ20220203

Experimental method

X-RAY DIFFRACTION (1.41800705321 Å)