General Information

Database accession: MF4100001

Name: Transthyretin (human)

PDB ID: 3a4d PDB

Experimental method: X-ray (2.00 Å)

Assembly: homotetramer (dimer of dimers)

Source organism: Homo sapiens

Primer 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 PubMed

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.


Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

thyroid hormone binding Interacting selectively and non-covalently with thyroxine (T4) or triiodothyronine (T3), tyrosine-based hormones produced by the thyroid gland. GeneOntology

identical protein binding Interacting selectively and non-covalently with an identical protein or proteins. GeneOntology

hormone activity The action characteristic of a hormone, any substance formed in very small amounts in one specialized organ or group of cells and carried (sometimes in the bloodstream) to another organ or group of cells in the same organism, upon which it has a specific regulatory action. The term was originally applied to agents with a stimulatory physiological action in vertebrate animals (as opposed to a chalone, which has a depressant action). Usage is now extended to regulatory compounds in lower animals and plants, and to synthetic substances having comparable effects; all bind receptors and trigger some biological process. GeneOntology

protein heterodimerization activity Interacting selectively and non-covalently with a nonidentical protein to form a heterodimer. GeneOntology

Biological process:

extracellular matrix organization A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of an extracellular matrix. GeneOntology

transport The directed movement of substances (such as macromolecules, small molecules, ions) or cellular components (such as complexes and organelles) into, out of or within a cell, or between cells, or within a multicellular organism by means of some agent such as a transporter, pore or motor protein. GeneOntology

cellular protein metabolic process The chemical reactions and pathways involving a specific protein, rather than of proteins in general, occurring at the level of an individual cell. Includes cellular protein modification. GeneOntology

retinol metabolic process The chemical reactions and pathways involving retinol, one of the three compounds that makes up vitamin A. GeneOntology

Cellular component:

extracellular space That part of a multicellular organism outside the cells proper, usually taken to be outside the plasma membranes, and occupied by fluid. GeneOntology

protein complex A stable macromolecular complex composed (only) of two or more polypeptide subunits along with any covalently attached molecules (such as lipid anchors or oligosaccharide) or non-protein prosthetic groups (such as nucleotides or metal ions). Prosthetic group in this context refers to a tightly bound cofactor. The component polypeptide subunits may be identical. GeneOntology

cytoplasm All of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. GeneOntology

extracellular exosome A membrane-bounded vesicle that is released into the extracellular region by fusion of the limiting endosomal membrane of a multivesicular body with the plasma membrane. Extracellular exosomes, also simply called exosomes, have a diameter of about 40-100 nm. GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 4 distinct polypeptide molecules

Chains: A, B, C, D

Notes: Chains C and D were generated from chains A and B respectively, using the biomatrices described in the original PDB file.

Number of unique protein segments: 1


Chain A

Name: Transthyretin

Source organism: Homo sapiens

Length: 127 residues

Sequence:Sequence according to PDB SEQRESGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE

UniProtKB AC: P02766 (positions: 21-147) UniProt Coverage: 86.4%

UniRef90 AC: UniRef90_P02766 (positions: 21-147) UniRef90

Chain B

Name: Transthyretin

Source organism: Homo sapiens

Length: 127 residues

Sequence:Sequence according to PDB SEQRESGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE

UniProtKB AC: P02766 (positions: 21-147) UniProt Coverage: 86.4%

UniRef90 AC: UniRef90_P02766 (positions: 21-147) UniRef90

Chain C

Name: Transthyretin

Source organism: Homo sapiens

Length: 127 residues

Sequence:Sequence according to PDB SEQRESGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE

UniProtKB AC: P02766 (positions: 21-147) UniProt Coverage: 86.4%

UniRef90 AC: UniRef90_P02766 (positions: 21-147) UniRef90

Chain D

Name: Transthyretin

Source organism: Homo sapiens

Length: 127 residues

Sequence:Sequence according to PDB SEQRESGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE

UniProtKB AC: P02766 (positions: 21-147) UniProt Coverage: 86.4%

UniRef90 AC: UniRef90_P02766 (positions: 21-147) UniRef90

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

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).

Related Structure(s) 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).

There are 273 related structures in the Protein Data Bank:





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