Structural properties of an amyloid precursor of 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.
McParland
Victoria J
VJ
School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT UK.
Kalverda
Arnout P
AP
Homans
Steve W
SW
Radford
Sheena E
SE
D000686:Amyloidosis / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011489:Protein Denaturation / Q000187:drug effects; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D014508:Urea / Q000494:pharmacology; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism*
D001613:beta 2-Microglobulin; D014508:Urea