Modeling Protein Homopolymeric Repeats: Possible Polyglutamine Structural Motifs For Huntington’s Disease

Richard H. Lathrop, Malcolm Casale, Douglas J. Tobias, J. Lawrence Marsh, and Leslie M. Thompson

We describe a prototype system (Poly-X) for assisting an expert user in modeling protein repeats. Poly-X reduces the large number of degrees of freedom required to specify a protein motif in complete atomic detail. The result is a small number of parameters that are easily understood by, and under the direct control of, a domain expert. The system was applied to the polyglutamine (poly-Q) repeat in the first exon of huntingtin, the gene implicated in Huntington’s disease. We present four poly-Q structural motifs: two poly-Q-sheet motifs (parallel and anti-parallel) that constitute plausible alternatives to a similar previously published poly-Q-sheet motif, and two novel poly-Q helix motifs. To our knowledge, helical forms of polyglutamine have not been proposed before. The motifs suggest that there may be several plausible aggregation structures for the intranuclear inclusion bodies which have been found in diseased neurons, and may help in the effort to understand the structural basis for Huntington’s disease.

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