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Pathogenic Mutations Induce Partial Structural Changes in the Native β-Sheet Structure of Transthyretin and
Kwang Hun Lim1, Anvesh K R Dasari1, Renze Ma2
1Department of Chemistry, East Carolina University , Greenville, North Carolina 27858, United States.
Biochemistry
|August 19, 2017
Summary
Transthyretin (TTR) amyloid formation involves protein unfolding. Solid-state NMR reveals structural differences in mutant TTR amyloids, particularly in the DA β-structure, explaining their increased aggregation propensity.
Area of Science:
- Biochemistry
- Structural Biology
- Biophysics
Background:
- Amyloid formation in proteins like transthyretin (TTR) is linked to disease and involves unfolding into aggregation-prone states.
- Understanding the structural basis of TTR aggregation is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the structural changes in wild-type (WT) and mutant TTR amyloids using solid-state NMR.
- To elucidate the structural differences that contribute to the enhanced aggregation of pathogenic TTR mutants.
Main Methods:
- Solid-state nuclear magnetic resonance (NMR) spectroscopy with selective 13C labeling.
- Analysis of 13C-13C correlation spectra to determine beta-sheet structures.
- Mass spectrometry for thermodynamic analysis of precursor states.
- Oxidation rate studies of methionine side chains.
Main Results:
- WT TTR amyloid core exhibits nativelike CBEF and DAGH beta-sheet structures.
- Mutant TTR amyloids (V30M, L55P) share nativelike CBEF and AGH beta-structures but show alterations in the DA beta-structure.
- The L55P mutation leads to increased disorder in strand D even in the native state.
- Mutant TTR precursor states are less stable than WT TTR.
- Met-30 side chain oxidation in V30M mutant suggests disruption of the DA beta-structure.
Conclusions:
- Pathogenic TTR mutations, particularly affecting the DA beta-structure, promote more effective amyloid formation.
- Structural destabilization of precursor states and disruption of specific beta-sheet structures correlate with increased TTR aggregation.
- Solid-state NMR provides detailed structural insights into TTR amyloid formation mechanisms.