Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited disease. Dystrophin, localized within a cytoplasmic lattice termed costameres, connects the intracellular cytoskeleton of a myofiber through the cell membrane (sarcolemma) to the surrounding extracellular matrix. In spite of its mechanical regulation roles in stabilizing the sarcolemma during muscle contraction, the underlying molecular mechanism is still elusive. Here, we systematically investigated the mechanical stability and kinetics of the force-bearing central domain of human dystrophin that contains 24 spectrin repeats using magnetic tweezers. We show that the stochastic unfolding and refolding of central domain of dystrophin is able to keep the forces below 25 pN over a significant length change up to ∼800 nm in physiological level of pulling speeds. These results suggest that dystrophin may serve as a molecular shock absorber that defines the physiological level of force in the dystrophin-mediated force-transmission pathway during muscle contraction/stretch, thereby stabilizing the sarcolemma.
Bibliographical noteFunding Information:
We thank the Mechanobiology Institute (MBI) protein expression facility for protein purification and MBI Science Communications core for illustrative animation and manuscript proofreading. The research is funded by the National Research Foundation, Prime Minister’s Office, Singapore, under its NRF Investigatorship Programme (NRF Investigator-ship award no. NRF-NRFI2016-03 to J.Y.), the Ministry of Education under the Research Centres of Excellence programme (to J.Y., in part), Human Frontier Science Program RGP00001/2016 grant (to J.Y., in part) and Singapore Ministry of Education Academic Research Fund Tier 3 (MOE2016-T3-1-002 to J.Y., in part).
- magnetic tweezers
- mechanical stability
- molecular shock absorber