Database accession: MF4100001
Name: Transthyretin (human)
PDB ID: 3a4d
Experimental method: X-ray (2.00 Å)
Assembly: Homotetramer
Source organism: Homo sapiens
Primary publication of the structure:
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.
(2010) Biochemistry 49: 114-23
PMID: 19950966
Abstract:
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.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
hormone activity hormone activity
identical protein binding identical protein binding
thyroid hormone binding thyroid hormone binding
Biological process:
purine nucleobase metabolic process purine nucleobase metabolic process
Cellular component:
azurophil granule lumen azurophil granule lumen
extracellular exosome extracellular exosome
extracellular region extracellular region
extracellular space extracellular space
Structural annotations of the participating protein chains.Entry contents: 4 distinct polypeptide molecules
Chains: A, B-2, B, A-2
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Transthyretin
Source organism: Homo sapiens
Length: 147 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
UniProtKB AC: P02766 (positions: 30-145)
Coverage: 78%
Name: Transthyretin
Source organism: Homo sapiens
Length: 147 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
UniProtKB AC: P02766 (positions: 30-144)
Coverage: 78%
Name: Transthyretin
Source organism: Homo sapiens
Length: 147 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
UniProtKB AC: P02766 (positions: 30-144)
Coverage: 78%
Name: Transthyretin
Source organism: Homo sapiens
Length: 147 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE
UniProtKB AC: P02766 (positions: 30-144)
Coverage: 78%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: HIUase/Transthyretin family
Evidence level: Direct evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
Transthyretin was shown in calorimetrics experiments to follow two-state folding/binding kinetics with the emergence of structure being linked to oligomerization (PMID:11152276).
Chain A:
N/A
Chain B:
N/A
Chain B-2:
N/A
Chain A-2:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
Download this entry's XML file (.xml)
Download this entry's JSON file (.json)
