Structure analysis of the proteins associated with polyA repeat expansion disorders

Abstract

Repeat regions are low-complexity regions in the human genome that largely code for intrinsic disorder in proteins. Expansions outside the normal thresholds in repeat regions are likely to be pathogenic, leading to the so-called repeat expansion diseases. There have been numerous studies on the most common group of repeat expansion diseases, which are the polyglutamine (polyQ) repeat expansion diseases, but there has been much less work done on the second-largest group of expansion repeats disorders, which involves the expansion of polyalanine (polyA) repeat tracts. In this article, we present a comprehensive study of the structural changes predicted using I-TASSER when comparing the wild type and enlarged structures of all known polyA expansion disorders. The results show that there is a reduction in α helices, an increase in extended strands in parallel and/or anti-parallel β-sheet conformation, an increase in random coils/loops and irregular elements, and a large increase in solvent-accessible surface area. When compared to the findings in polyQ expansions disorders we see similar trends, suggesting that the polyQ and polyA repeat expansion causes similar effects on the respective proteins, which lead to higher misfolding and aggregation propensities.

Communicated by Ramaswamy H. Sarma

Keywords:

• Poly alanine disorders
• protein structure
• tandem repeat disorders

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work has been partially supported by the Utah Center for Clinical and Translational Science funded by NCATS award 1ULTR002538 and the NLM Training grant T15 LM00712418. Computer resources were provided by the University of Utah Center for High-Performance Computing, which has been partially funded by the NIH Shared Instrumentation Grant 1S10OD02164401A1.