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Abstract
Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are two common autosomal-dominant inherited ataxia syndromes, both of which are related to the unstable expansion of trinucleotide CAG repeats in the coding region of the related ATXN2 and ATXN3 genes, respectively. The poly-glutamine (poly-Q) tract encoded by the CAG repeats has long been recognized as an important factor in disease pathogenesis and progress. In this study, using the I-TASSER method for 3D structure prediction, we investigated the effect of poly-Q tract enlargement on the structure and folding of ataxin-2 and ataxin-3 proteins. Our results show good agreement with the known experimental structures of the Josephin and UIM domains providing credence to the simulation results presented here, which show that the enlargement of the poly-Q region not only affects the local structure of these regions but also affects the structures of functional domains as well as the whole protein. The changes observed in the predicted models of the UIM domains in ataxin-3 when the poly-Q track is enlarged provide new insights on possible pathogenic mechanisms.
Acknowledgements
Molecular graphics used the UCSF Chimera package developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). Computer time was provided by an allocation to JCF at the CHPC of the University of Utah. JCF has been partially supported by the University of Utah Center for Clinical and Translational Science under NCATS Grant 1ULTR001067. JW was partially supported by the Richard A. Fay and Carole M. Fay Endowed Graduate Fellowship for the Department of Biomedical Informatics in honor of Homer R. Warner, MD, PhD. We thank Professor Stefan Pulst for reading the manuscript.