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Structure analysis of the proteins associated with polyA repeat expansion disorders
Rolando Hernandez1, Julio C Facelli1,2
1Department of Biomedical Informatics, The University of Utah, Salt Lake City, UT, USA.
Journal of Biomolecular Structure & Dynamics
|January 18, 2021
Summary
Polyalanine (polyA) repeat expansions in proteins cause significant structural changes, including reduced alpha helices and increased beta sheets. These changes in polyA expansion disorders mirror those in polyglutamine (polyQ) diseases, suggesting similar aggregation risks.
Area of Science:
- Genomics
- Structural Biology
- Biochemistry
Background:
- Repeat regions in the human genome can cause disease when expanded beyond normal limits.
- Polyglutamine (polyQ) repeat expansion diseases are well-studied, but polyalanine (polyA) repeat expansion disorders are less understood.
- Protein intrinsic disorder is often associated with low-complexity repeat regions.
Purpose of the Study:
- To comprehensively study the structural changes in polyalanine (polyA) repeat expansion disorders.
- To compare the structural impact of polyA expansions with known effects of polyglutamine (polyQ) expansions.
- To predict structural alterations using the I-TASSER computational tool.
Main Methods:
- Utilized I-TASSER for in silico structural prediction.
- Compared wild-type and expanded protein structures for all known polyA expansion disorders.
- Analyzed changes in secondary structure elements (α-helices, β-sheets) and solvent accessibility.
Main Results:
- Observed a reduction in α-helices and an increase in β-sheet structures (parallel and/or anti-parallel).
- Noted an increase in random coils/loops and irregular structural elements.
- Documented a significant increase in solvent-accessible surface area in expanded polyA structures.
Conclusions:
- PolyA repeat expansions induce significant protein structural destabilization.
- The observed structural changes in polyA disorders are analogous to those in polyQ disorders.
- Both polyA and polyQ repeat expansions likely increase protein misfolding and aggregation propensities.
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