1GKO

An Engineered Transthyretin Monomer that is Non-amyloidogenic - Unless Partially Denatured

Summary for 1GKO

• Entry DOI: 10.2210/pdb1gko/pdb
• Related: 1BM7 1BMZ 1BZ8 1BZD 1BZE 1E3F 1E4H 1E5A 1ETA 1ETB 1F41 1F64 1F86 1FH2 1FHN 1RLB 1THA 1THC 1TLM 1TSH 1TTA 1TTB 1TTC 1TTR 1TYR 2PAB 2ROX 2ROY 2TRH 2TRY 5TTR
• Descriptor: TRANSTHYRETIN (2 entities in total)
• Functional Keywords: transport(thyroxine), transthyretin, ttr, mutant monomer transthyretin, mutant monomer ttr, amyloid forming protein, amyloid
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 4
• Total formula weight: 55117.68

Authors

Jiang, X.,Smith, C.S.,Petrassi, H.M.,Hammarstrom, P.,White, J.T.,Sacchettini, J.C.,Kelly, J.W. (deposition date: 2001-08-17, release date: 2001-11-28, Last modification date: 2023-12-13)

Primary citation

Jiang, X.,Smith, C.S.,Petrassi, H.M.,Hammarstrom, P.,White, J.T.,Sacchettini, J.C.,Kelly, J.W.
An Engineered Transthyretin Monomer that is Nonamyloidogenic, Unless It is Partially Denatured
Biochemistry, 40:11442-, 2001

PubMed Abstract: Transthyretin (TTR) is a soluble human plasma protein that can be converted into amyloid by acid-mediated dissociation of the homotetramer into monomers. The pH required for disassembly also results in tertiary structural changes within the monomeric subunits. To understand whether these tertiary structural changes are required for amyloidogenicity, we created the Phe87Met/Leu110Met TTR variant (M-TTR) that is monomeric according to analytical ultracentrifugation and gel filtration analyses and nonamyloidogenic at neutral pH. Results from far- and near-UV circular dichroism spectroscopy, one-dimensional proton NMR spectroscopy, and X-ray crystallography, as well as the ability of M-TTR to form a complex with retinol binding protein, indicate that M-TTR forms a tertiary structure at pH 7 that is very similar if not identical to that found within the tetramer. Reducing the pH results in tertiary structural changes within the M-TTR monomer, rendering it amyloidogenic, demonstrating the requirement for partial denaturation. M-TTR exhibits stability toward acid and urea denaturation that is nearly identical to that characterizing wild-type (WT) TTR at low concentrations (0.01-0.1 mg/mL), where monomeric WT TTR is significantly populated at intermediate urea concentrations prior to the tertiary structural transition. However, the kinetics of denaturation and fibril formation are much faster for M-TTR than for tetrameric WT TTR, particularly at near-physiological concentrations, because of the barrier associated with the tetramer to folded monomer preequilibrium. These results demonstrate that the tetramer to folded monomer transition is insufficient for fibril formation; further tertiary structural changes within the monomer are required.

PubMed: 11560492
DOI: 10.1021/BI011194D

Experimental method

X-RAY DIFFRACTION (2.1 Å)