Mutations in Duchenne muscular dystrophy (DMD) gene that affect the expression of dystrophin protein lead to a number of disorders collectively called dystrophinopathies characterized by muscle degeneration and loss. Dystrophin is a large protein (427 KDa) made up of N-terminal calponin homology (CH) domains, 24 spectrin repeats, cystein rich (CR) domain and C-terminal (CT) domain. Numerous isoforms of dystrophin are known to exist due to alternative splicing and usage of alternate promoters. These variations occur in the functionally important N-terminal and the C-terminal domains. The N-terminal domain mediates interaction with actin, whereas the C-terminal domain interacts with cytosolic proteins like dystrobrevin and syntrophin. The impact of these isoform variations on the structure and function of dystrophin is unexplored. Dystrophin isoforms have differing tissue specificity and thus the differences in their structure-function become important in understanding tissue specific symptoms of dystrophinopathies. We probed the impact of these variations on structure-function relationship of dystrophin. We found that minor N-terminal variations in the CH domain of dystrophin isoforms modulate their thermodynamic stability and actin-binding function, thus leading to specificity in dystrophin-actin interactions in various tissues. We also characterized the yet unexplored CT domain of dystrophin, and the variations in the CT domain of dystrophin lead to differences in the stability and binding specificity towards its binding partners. These results show that sequence variations in tissue specific isoforms do govern thermodynamic stabilities, thus affecting tissue-specific dystrophin expression, and dystrophin interaction networks. These differences should be considered before designing effective therapeutic strategies for dystrophinopathies that specifically affect different tissues with a myriad of symptoms.

Tissue-specific dystrophin isoforms have different stabilities and functional roles

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.