Structural properties of an amyloid precursor of β2-microglobulin

• DOI: 10.1038/nsb791
• Publication Date: 2002-07-26T08:54:57Z
• Authors: Victoria J. McPar...; Arnout P. Kalverda; Steve W. Homans; Sheena E. Radford
• Keywords: Models, Molecular; 0301 basic medicine; Protein Denaturation; Protein Folding; 03 medical and health sciences; Magnetic Resonance Spectroscopy; Humans; Urea; Amyloidosis; Hydrogen-Ion Concentration; Protein Structure, Quaternary; beta 2-Microglobulin

The population of one or more partially folded states has been proposed as a critical initial step in amyloid formation for several proteins. Here we use equilibrium denaturation measured by (1)H-(15)N NMR to determine the conformational properties of an amyloidogenic intermediate of human beta(2)-microglobulin (beta(2)m) formed at low pH. The data show that this amyloid precursor is a noncooperatively stabilized ensemble that retains stable structure in five of the seven beta-strands that comprise the native fold. The amyloid precursors of beta(2)m and transthyretin have similar properties despite having structurally unrelated native folds. The data offer a rationale as to why these proteins are both amyloidogenic at low pH and suggest that amyloidosis of these and other proteins may involve ordered assembly from a precursor with similar conformational features.