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Dystrophin is a rod shaped protein consisting of amino- and carboxy- terminal binding domains linked by a large central rod composed of 24 homologous copies of the STR motif and 4 non-homologous regions termed hinges. The binding domains serve toMoreDystrophin is a rod shaped protein consisting of amino- and carboxy- terminal binding domains linked by a large central rod composed of 24 homologous copies of the STR motif and 4 non-homologous regions termed hinges. The binding domains serve to link F-actin in the myocyte contractile machinery to a docking point in the myocyte membrane, stabilizing the cell. The central rod domain determines the mechanical properties of this linkage, with the hinges proposed to provide flexibility- the tacit implication is that the STR regions of the rod, away from the hinges, are comparatively rigid. The STRs are repeating and homologous, which has contributed to the view that they are uniform and monolithic. However, we have produced nearly all single and double STR fragments and showed that they exhibit markedly different stabilities, and that some regions appear disordered and perhaps flexible.-The so-called hinge regions are identified on their lack of homology alone with no further biophysical characterization. However, we confirmed their instability and suggest that these less stable STRs function as possible hinge-like regions according to biophysical and biochemical characteristics unveiled during this work.-A full understanding of how these properties vary along the length of the rod has implications for the engineering of these rods regions in exon-skipping and mini-dystrophin therapies. Exon skipping repair is a strategy being investigated in early stage clinical trials to treat Duchenne muscular dystrophy. This work has implications for the design of optimal therapeutic exon skipping strategies.