Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin

Jean A. Hamilton, Larry K. Steinrauf, Juris Liepnieks, Merrill D. Benson, Gosta Holmgren, Olan Sandgren, Lars Steen

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 Å resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 Å. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalBBA - Molecular Basis of Disease
Volume1139
Issue number1-2
DOIs
StatePublished - Jun 9 1992

Keywords

  • Beta-sheet protein
  • Familial amyloidosis
  • Met-30 transthyretin variant
  • X-ray crystal structure

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology
  • Molecular Medicine

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