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Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity
Per Hammarström1, Xin Jiang, Amy R Hurshman
1Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road BCC265, La Jolla, CA 92037, USA.
Summary
Protein mutations significantly impact amyloid disease severity by altering transthyretin (TTR) tetramer dissociation rates. Rapid dissociation exacerbates disease, while slow dissociation reduces amyloidogenicity, influencing disease penetrance and onset.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Amyloidosis arises from protein misfolding and self-assembly into amyloid fibrils.
- Single point mutations in amyloidogenic proteins like transthyretin (TTR) can drastically alter disease phenotypes.
- Thermodynamic stability alone is insufficient to predict amyloidosis severity.
Purpose of the Study:
- To investigate how specific mutations in transthyretin (TTR) influence the rate of tetramer dissociation.
- To correlate TTR tetramer dissociation kinetics with amyloid formation, disease penetrance, and age of onset.
- To elucidate the role of mutation-induced kinetic and thermodynamic changes in the phenotypic diversity of amyloid diseases.
Main Methods:
- Analysis of transthyretin (TTR) tetramer dissociation rates for various mutations (V30M, L55P, T119M, V122I) and wild type (WT).
- Correlation of dissociation kinetics with thermodynamic stability and observed disease phenotypes.
- Examination of T119M homotetramer's kinetic stabilization properties.
Main Results:
- Mutation rates of TTR tetramer dissociation strongly influence amyloidogenicity, with faster rates exacerbating disease.
- L55P TTR shows severe pathology due to rapid dissociation and destabilization.
- V122I TTR exhibits increased penetrance due to a higher dissociation rate, despite similar stability to WT.
- T119M TTR demonstrates kinetic stabilization, dissociating slowly and potentially protecting against disease.
Conclusions:
- TTR tetramer dissociation kinetics are critical determinants of amyloid disease severity, penetrance, and onset.
- Understanding both kinetics and thermodynamics of protein misfolding is essential for explaining amyloid disease variability.
- Specific mutations can kinetically stabilize TTR, offering protection against amyloidosis.