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Structural properties of an amyloid precursor of beta(2)-microglobulin
Victoria J McParland1, Arnout P Kalverda, Steve W Homans
1School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT UK.
Abstract:
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.
Insights
Partially folded protein states initiate amyloid formation. Researchers studied human beta(2)-microglobulin (beta(2)m) using NMR, finding its amyloid precursor retains significant native structure, explaining its low pH amyloidogenicity.
Area of Science:
- Biochemistry
- Structural Biology
- Medical Biochemistry
Background:
- Amyloid formation is linked to partially folded protein states.
- Human beta(2)-microglobulin (beta(2)m) is associated with amyloidosis, particularly at low pH.
Purpose of the Study:
- To determine the conformational properties of the amyloidogenic intermediate of human beta(2)m.
- To understand the structural basis for beta(2)m amyloid formation at low pH.
Main Methods:
- Equilibrium denaturation experiments.
- (1)H-(15)N Nuclear Magnetic Resonance (NMR) spectroscopy to analyze protein structure.
Main Results:
- The amyloid precursor of beta(2)m is a noncooperatively stabilized ensemble.
- This intermediate retains stable structure in five of its seven native beta-strands.
- Amyloid precursors of beta(2)m and transthyretin share similar conformational properties despite different native folds.
Conclusions:
- The findings provide a rationale for the low pH amyloidogenicity of beta(2)m and transthyretin.
- Amyloidosis may involve ordered assembly from precursors with conserved conformational features.
- Partially folded protein intermediates play a critical role in initiating amyloid formation.