2H4E

Crystal structure of Cys10 sulfonated transthyretin

Summary for 2H4E

• Entry DOI: 10.2210/pdb2h4e/pdb
• Descriptor: Transthyretin, SULFATE ION (3 entities in total)
• Functional Keywords: amyloid, sulfite, transthyretin, familial amyloidotic polyneuropathy, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27810.91

Authors

Gales, L.,Damas, A.M. (deposition date: 2006-05-24, release date: 2007-01-23, Last modification date: 2023-08-30)

Primary citation

Gales, L.,Saraiva, M.J.,Damas, A.M.
Structural basis for the protective role of sulfite against transthyretin amyloid formation.
Biochim.Biophys.Acta, 1774:59-64, 2007

PubMed Abstract: Transthyretin (TTR) is a plasma protein, which under conditions not yet completely understood, aggregates forming amyloid deposits that occur extracellularly. It is a protein composed of four identical subunits. Each monomer has a single cysteine residue (Cys10), which in the plasma is reduced (Cys-SH), oxidized (Cys-SO3-), sulfonated (Cys-S-SO3-) or bound to various sulfhydryls. There is evidence that these chemical modifications of the SH group alter the stability and the amyloidogenic potential of the protein. The sulfonated form was found to enhance the stability of the native conformation of TTR, avoiding misassembly of the protein leading to amyloid. Consequently, the potential treatment of TTR-type amyloidosis by sulfite has been suggested. The structure of TTR pre-incubated with sulfite at physiological pH, was determined by X-ray crystallography to provide structural insight for the stabilizing effect of sulfite. Each subunit has a beta-sandwich conformation, with two four stranded beta-pleated sheets (DAGH and CBEF) and a small alpha-helix between strands. The sulfonated cysteines have two sulfite oxygens involved in intramonomer hydrogen bonds that bridge Cys10, the amino acid immediately before beta-strand A, to the amino acids immediately after the edge beta-strand D. Implications of the newly observed interactions in the inhibition of fibril formation are discussed in light of the recent structural models of TTR amyloid fibrils.

PubMed: 17175208
DOI: 10.1016/j.bbapap.2006.10.015

Experimental method

X-RAY DIFFRACTION (1.45 Å)