SAXS OF DRYSTROPHIN FRAGMENTS

Illinois Institute Of Technology, Chicago IL

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. These studies are part of an NIH funded project to determine the domain structure and biophysical properties of the dystrophin rod infamous for its role in Duchenne Muscular Dystrophy. SAXS will be used to determine the structure of various dystrophin rod fragments to determine their shape and flexibility;the aim is to identify rod regions that contain hinges or kinks that disrupt the rod. The fundamental building block of the rod region is the spectrin type repeat, STR, an ~100 amino acid motif present in 24 tandem copies. STRs fold to form zigzag triple a-helical bundle structures with three a-helices in a zigzag arrangement that places the ends of the polypeptide chain at opposite ends of this bundle. Tandem arrangement of STRs thus produces a long, rod shaped molecule. In some regions, adjacent STRs form interacting structures. This has led to the development a of a nested model, in which the three helices of STR bundles are thought of not as (ABC)(ABC)(ABC) , but as A)B(CA)B(CA)B . In this conception, a continuous, long CA helix alternates with a half-size, antiparallel B helix in a two-steps-forward-one-step-back rod, and the exact biophysical domain boundaries are unclear. Although these two models were once rivals, it now seems that both may be applicable in different regions of the rod, possibly leading to very different rod rigidities. However, there is has never been any direct measurement of rod shape or rigidity, which is the aim of our studies.