Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy

A. Olofsson, J.H. Ippel, S.S. Wijmenga, E. Lundgren, A. Ohman

Research output: Contribution to journalArticleAcademicpeer-review

100 Citations (Scopus)


The human plasma protein transthyretin (TTR) may form fibrillar protein deposits that are associated with both inherited and idiopathic amyloidosis. The present study utilizes solution nuclear magnetic resonance spectroscopy, in combination with hydrogen/deuterium exchange, to determine residue-specific solvent protection factors within the fibrillar structure of the clinically relevant variant, TTRY114C. This novel approach suggests a fibril core comprised of the six beta-strands, A-B-E-F-G-H, which retains a native-like conformation. Strands C and D are dislocated from their native edge region and become solvent-exposed, leaving a new interface involving strands A and B open for intermolecular interactions. Our results further support a native-like intermolecular association between strands F-F' and H-H' with a prolongation of these beta-strands and, interestingly, with a possible shift in beta-strand register of the subunit assembly. This finding may explain previous observations of a monomeric intermediate preceding fibril formation. A structural model based on our results is presented.
Original languageEnglish
Pages (from-to)5699-5707
JournalJournal of Biological Chemistry
Issue number7
Publication statusPublished - 2004


  • hydrogen-exchange
  • tetramer dissociation
  • subunit interface
  • x-ray
  • fibrils
  • core
  • intermediate
  • proteins
  • variants
  • mutants


Dive into the research topics of 'Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy'. Together they form a unique fingerprint.

Cite this