Dystrophin As a Molecular Shock Absorber

Shimin Le; Miao Yu; Ladislav Hovan; Zhihai Zhao; James Ervasti; Jie Yan

doi:10.1021/acsnano.8b05721

Dystrophin As a Molecular Shock Absorber

Shimin Le, Miao Yu, Ladislav Hovan, Zhihai Zhao, James Ervasti, Jie Yan

Metabolic and Systems Biology (TMED)

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	12140-12148
Number of pages	9
Journal	ACS nano
Volume	12
Issue number	12
DOIs	https://doi.org/10.1021/acsnano.8b05721
State	Published - Dec 26 2018

Bibliographical note

Funding 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).

Publisher Copyright:
© 2018 American Chemical Society.

Keywords

dystrophin
magnetic tweezers
mechanical stability
molecular shock absorber
sarcolemma

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10.1021/acsnano.8b05721

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632074

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title = "Dystrophin As a Molecular Shock Absorber",

abstract = "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.",

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author = "Shimin Le and Miao Yu and Ladislav Hovan and Zhihai Zhao and James Ervasti and Jie Yan",

note = "Funding 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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

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N1 - Funding 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). Publisher Copyright: © 2018 American Chemical Society.

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N2 - 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.

AB - 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.

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Dystrophin As a Molecular Shock Absorber

Abstract

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