MF4100001
Transthyretin (human)
3a4d
X-ray
2.00
homotetramer (dimer of dimers)
Homo sapiens
19950966
Miyata M, Sato T, Mizuguchi M, Nakamura T, Ikemizu S, Nabeshima Y, Susuki S, Suwa Y, Morioka H, Ando Y, Suico MA, Shuto T, Koga T, Yamagata Y, Kai H
Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding.
Biochemistry
2010
1
49
114-23
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.
GO:0070324
thyroid hormone binding
GO:0042802
identical protein binding
GO:0005179
hormone activity
GO:0046982
protein heterodimerization activity
GO:0030198
extracellular matrix organization
GO:0006810
transport
GO:0044267
cellular protein metabolic process
GO:0042572
retinol metabolic process
GO:0005615
extracellular space
GO:0043234
protein complex
GO:0005737
cytoplasm
GO:0070062
extracellular exosome
Chains C and D were generated from chains A and B respectively, using the biomatrices described in the original PDB file.
4
1
Transthyretin-like folds
Transthyretin
A
Transthyretin
Homo sapiens
GPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
127
P02766
21
147
86.4%
UniRef90_P02766
21
147
secondary structure
beta
32
38
secondary structure
beta
43
44
secondary structure
beta
49
55
secondary structure
beta
61
68
secondary structure
beta
74
75
secondary structure
beta
87
93
secondary structure
helix
95
101
secondary structure
beta
108
117
secondary structure
beta
124
132
secondary structure
beta
135
143
pfam
PF00576.18
Transthyretin
32
139
B
Transthyretin
Homo sapiens
GPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
127
P02766
21
147
86.4%
UniRef90_P02766
21
147
secondary structure
beta
32
38
secondary structure
beta
43
44
secondary structure
beta
49
55
secondary structure
beta
61
68
secondary structure
beta
74
75
secondary structure
beta
87
93
secondary structure
helix
95
101
secondary structure
beta
108
117
secondary structure
beta
124
132
secondary structure
beta
135
143
pfam
PF00576.18
Transthyretin
32
139
C
Transthyretin
Homo sapiens
GPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
127
P02766
21
147
86.4%
UniRef90_P02766
21
147
secondary structure
beta
32
38
secondary structure
beta
43
44
secondary structure
beta
49
55
secondary structure
beta
61
68
secondary structure
beta
74
75
secondary structure
beta
87
93
secondary structure
helix
95
101
secondary structure
beta
108
117
secondary structure
beta
124
132
secondary structure
beta
135
143
pfam
PF00576.18
Transthyretin
32
139
D
Transthyretin
Homo sapiens
GPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
127
P02766
21
147
86.4%
UniRef90_P02766
21
147
secondary structure
beta
32
38
secondary structure
beta
43
44
secondary structure
beta
49
55
secondary structure
beta
61
68
secondary structure
beta
74
75
secondary structure
beta
87
93
secondary structure
helix
95
101
secondary structure
beta
108
117
secondary structure
beta
124
132
secondary structure
beta
135
143
pfam
PF00576.18
Transthyretin
32
139
Transthyretin was shown in calorimetrics experiments to follow two-state folding/binding kinetics with the emergence of structure being linked to oligomerization (PMID:11152276).
1bm7
1bmz
1bz8
1bzd
1bze
1dvq
1dvs
1dvt
1dvu
1dvx
1dvy
1dvz
1e3f
1e4h
1e5a
1eta
1etb
1f41
1f86
1fh2
1fhn
1g1o
1gko
1ict
1iii
1iik
1ijn
1qab
1qwh
1rlb
1sok
1soq
1tha
1thc
1tlm
1tsh
1tt6
1tta
1ttb
1ttc
1ttr
1tyr
1tz8
1u21
1x7s
1x7t
1y1d
1z7j
1zcr
1zd6
2b14
2b15
2b16
2b77
2b9a
2f7i
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2fbr
2flm
2g3x
2g3z
2g4e
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2g5u
2g9k
2gab
2h4e
2nbo
2nbp
2noy
2pab
2qel
2qgb
2qgc
2qgd
2qge
2rox
2roy
2trh
2try
2wqa
3a4e
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3b56
3bsz
3bt0
3cbr
3cfm
3cfn
3cfq
3cft
3cn0
3cn1
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3cxf
3d2t
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3dgd
3did
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3do4
3esn
3eso
3esp
3fc8
3fcb
3glz
3gps
3grb
3grg
3gs0
3gs4
3gs7
3hj0
3i9a
3i9i
3i9p
3imr
3ims
3imt
3imu
3imv
3imw
3ipb
3ipe
3kgs
3kgt
3kgu
3m1o
3nee
3neo
3nes
3nex
3ng5
3ozk
3ozl
3p3r
3p3s
3p3t
3p3u
3ssg
3tct
3tfb
3u2i
3u2j
3w3b
4abq
4abu
4abv
4abw
4ac2
4ac4
4act
4ank
4d7b
4der
4des
4det
4deu
4dew
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4i85
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4iki
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4l1s
4l1t
4mas
4mrb
4mrc
4n85
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4pm1
4pme
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4pvl
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4pwe
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4pwj
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4qya
4tkw
4tl4
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4tls
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4tlu
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4tq8
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4wnj
4wns
4wo0
4y9b
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4ydm
4ydn
5a6i
5aks
5akt
5akv
5al0
5al8
5ayt
5boj
5clx
5cly
5clz
5cm1
5cn3
5cnh
5cr1
5dej
5dwp
5e23
5e4a
5e4o
5en3
5ezp
5fo2
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5fw8
5hjg
5ihh
5jid
5jim
5jiq
5k1j
5k1n
5l4f
5l4i
5l4j
5l4m
5ttr