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PDBsum entry 3a4d
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Transport protein
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PDB id
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3a4d
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References listed in PDB file
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Key reference
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Title
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Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding.
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Authors
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M.Miyata,
T.Sato,
M.Mizuguchi,
T.Nakamura,
S.Ikemizu,
Y.Nabeshima,
S.Susuki,
Y.Suwa,
H.Morioka,
Y.Ando,
M.A.Suico,
T.Shuto,
T.Koga,
Y.Yamagata,
H.Kai.
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Ref.
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Biochemistry, 2010,
49,
114-123.
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PubMed id
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Abstract
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Transthyretin (TTR) is a tetrameric protein associated with amyloidosis caused
by tetramer dissociation and monomer misfolding. The structure of two TTR
variants (E54G and E54K) with Glu54 point mutation that cause clinically
aggressive amyloidosis remains unclear, although amyloidogenicity of artificial
triple mutations (residues 53-55) in beta-strand D had been investigated. Here
we first analyzed the crystal structures and biochemical and biophysical
properties of E54G and E54K TTRs. The direction of the Lys15 side chain in E54K
TTR and the surface electrostatic potential in the edge region in both variants
were different from those of wild-type TTR. The presence of Lys54 leads to
destabilization of tetramer structure due to enhanced electrostatic repulsion
between Lys15 of two monomers. Consistent with structural data, the biochemical
analyses demonstrated that E54G and E54K TTRs were more unstable than wild-type
TTR. Furthermore, the entrance of the thyroxine (T(4)) binding pocket in TTR was
markedly narrower in E54K TTR and wider in E54G TTR compared with wild-type TTR.
The tetramer stabilization and amyloid fibril formation assays in the presence
of T(4) showed lower tetramer stability and more fibril formation in E54K and
E54G TTRs than in wild-type TTR, suggesting decreased T(4) binding to the TTR
variants. These findings indicate that structural modification by Glu54 point
mutation may sufficiently alter tetramer stability and T(4) binding.
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