Stability of dystrophin STR fragments in relation to junction helicity.
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. These hinges are proposed to confer local flexibility; conversely, the tacit implication is that the STR regions away from the hinges are comparatively rigid. This, and the repeating nature of this rod, has contributed to the view that the STR region of the rod is uniform and monolithic. However, we have produced various 2 STR fragments, chosen to have high and low alpha-helix content at their junctions with each other, and show that they exhibit markedly different stabilities. In contrast to a related protein, spectrin, these differences are not correlated with the calculated helicity, but appear to be an intrinsic property of the motifs themselves. 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 minidystrophin therapies.
Mirza
Ahmed
A
Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, 3101 South Dearborn, Chicago, IL 60616, USA.
Menhart
Nick
N
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D004355:Drug Stability; D016189:Dystrophin / Q000737:chemistry* / Q000235:genetics; D019286:Endopeptidase K; D006801:Humans; D008027:Light; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
C484258:DMD protein, human; D016189:Dystrophin; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019286:Endopeptidase K