PDBsum entry 2qpf

Transport protein

PDB id: 2qpf

Contents

Protein chains

(+ 2 more) 117 a.a. *

Waters ×347

* Residue conservation analysis

PDB id:

2qpf

Name:

Transport protein

Title:

Crystal structure of mouse transthyretin

Structure:

Transthyretin. Chain: a, b, c, d, e, f, g, h. Synonym: prealbumin. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: ttr. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.05Å R-factor: 0.200 R-free: 0.246

Authors:

N.Reixach,T.R.Foss,E.Santelli,J.Pascual,J.W.Kelly,J.N.Buxbaum

Key ref:

N.Reixach et al. (2008). Human-Murine Transthyretin Heterotetramers Are Kinetically Stable and Non-amyloidogenic: A LESSON IN THE GENERATION OF TRANSGENIC MODELS OF DISEASES INVOLVING OLIGOMERIC PROTEINS. J Biol Chem, 283, 2098-2107. PubMed id: 18006495 DOI: 10.1074/jbc.M708028200

Date:

23-Jul-07 Release date: 27-Nov-07

Protein chains

P07309  (TTHY_MOUSE) -  Transthyretin from Mus musculus

Seq: 147 a.a.

Struc: 117 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.M708028200

J Biol Chem 283:2098-2107 (2008)

PubMed id: 18006495

Human-Murine Transthyretin Heterotetramers Are Kinetically Stable and Non-amyloidogenic: A LESSON IN THE GENERATION OF TRANSGENIC MODELS OF DISEASES INVOLVING OLIGOMERIC PROTEINS.

N.Reixach, T.R.Foss, E.Santelli, J.Pascual, J.W.Kelly, J.N.Buxbaum.

ABSTRACT

The transthyretin amyloidoses appear to be caused by rate-limiting tetramer dissociation and partial monomer unfolding of the human serum protein transthyretin, resulting in aggregation and extracellular deposition of amorphous aggregates and amyloid fibrils. Mice transgenic for few copies of amyloid-prone human transthyretin variants, including the aggressive L55P mutant, failed to develop deposits. Silencing the murine transthyretin gene in the presence of the L55P human gene resulted in enhanced tissue deposition. To test the hypothesis that the murine protein interacted with human transthyretin, preventing the dissociation and partial unfolding required for amyloidogenesis, we produced recombinant murine transthyretin and human/murine transthyretin heterotetramers and compared their structures and biophysical properties to recombinant human transthyretin. We found no significant differences between the crystal structures of murine and human homotetramers. Murine transthyretin is not amyloidogenic because the native homotetramer is kinetically stable under physiologic conditions and cannot dissociate into partially unfolded monomers, the misfolding and aggregation precursor. Heterotetramers composed of murine and human subunits are also kinetically stable. These observations explain the lack of transthyretin deposition in transgenics carrying a low copy number of human transthyretin genes. The incorporation of mouse subunits into tetramers otherwise composed of human amyloid-prone transthyretin subunits imposes kinetic stability, preventing dissociation and subsequent amyloidogenesis.

Selected figure(s)

Figure 1.
FIGURE 1. A, primary structure alignment of Hu-TTR and Mu-TTR. Stars at the bottom indicate identical amino acid residues. B, two views of the crystal structure of Mu-TTR superimposed on that of Hu-TTR. Each mouse TTR subunit is shown in a different color; Hu-TTR is shown in gray. Dashed lines indicate the dimer interfaces, and the crystallographic C[2] x axis is labeled.

Figure 4.
FIGURE 4. Kinetics of tetramer disassembly (closed symbols) and unfolding (open symbols) in 6 M urea for Hu-TTR (triangles) and Mu-TTR (circles). For both Hu-TTR and Mu-TTR the loss of quaternary structure (disassembly) and the loss of tertiary structure (unfolding) are tightly linked. Mu-TTR is kinetically stabilized compared with Hu-TTR as seen by its significantly slower dissociation/unfolding kinetics. Tetramer disassembly was measured by resveratrol binding fluorescence; unfolding was measured by tryptophan fluorescence.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 2098-2107) copyright 2008.

Figures were selected by the author.