ArticleProceedings of the National Academy of Sciences of the United States of America2013
α2 and α3 helices of dystrophin R16 and R17 frame a microdomain in the α1 helix of dystrophin R17 for neuronal NOS binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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64 citing papers in PubMed, 86 citations in OpenAlex.
- The atomic structure of human dystrophin spectrin-like repeat 24.Acta crystallographica. Section F, Structural biology communications · 2026Article
- AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects.Gene therapy · 2025Review
- Caveolin and NOS in the Development of Muscular Dystrophy.International journal of molecular sciences · 2024Review
- Why is early-onset atrial fibrillation uncommon in patients with Duchenne muscular dystrophy? Insights from the mdx mouse.Cardiovascular research · 2024Article
- Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers.Neuromuscular disorders : NMD · 2024Article
- Assessment of Therapeutic Potential of a Dual AAV Approach for Duchenne Muscular Dystrophy.International journal of molecular sciences · 2023Article
- Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy.International journal of molecular sciences · 2023Article
- Lifelong Outcomes of Systemic Adeno-Associated Virus Micro-Dystrophin Gene Therapy in a Murine Duchenne Muscular Dystrophy Model.Human gene therapy · 2023Article
- Prolonged voluntary wheel running reveals unique adaptations in mdx mice treated with microdystrophin constructs ± the nNOS-binding site.Frontiers in physiology · 2023Article
- Evolution and developmental functions of the dystrophin-associated protein complex: beyond the idea of a muscle-specific cell adhesion complex.Frontiers in cell and developmental biology · 2023Review
- Histological Assessment of Gene Therapy in the Canine DMD Model.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy.International journal of molecular sciences · 2022Review
- Review
- Targeting IRES-dependent translation as a novel approach for treating Duchenne muscular dystrophy.RNA biology · 2021Review
- Dystrophin deficiency impairs vascular structure and function in the canine model of Duchenne muscular dystrophy.The Journal of pathology · 2021Article
- The multifaceted view of heart problem in Duchenne muscular dystrophy.Cellular and molecular life sciences : CMLS · 2021Review
- Dose-Escalation Study of Systemically Delivered rAAVrh74.MHCK7.micro-dystrophin in theHuman gene therapy · 2021Article
- Duchenne muscular dystrophy.Nature reviews. Disease primers · 2021Review
- Gene Therapy for Duchenne Muscular Dystrophy.Journal of neuromuscular diseases · 2021Review
- Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy.Cells · 2020Article
4 more citing papers are in PubMed but not listed here.
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4 authors at 1 institution in 1 country.
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Abstract
Homologous spectrin-like repeats can mediate specific protein interaction. The underlying mechanism is poorly understood. Dystrophin contains 24 spectrin-like repeats. However, only repeats 16 and 17 (R16/17) are required for anchoring neuronal NOS (nNOS) to the sarcolemma. Through an adeno-associated virus-based in vivo binding assay, we found that membrane expression of correctly phased R16/17 was sufficient to recruit nNOS to the sarcolemma in mouse muscle. Utrophin R15/16 is homologous to dystrophin R16/17. Substitution of dystrophin R16/17 microdomains with the corresponding regions of utrophin R15/16 suggests that the nNOS binding site is located in a 10-residue fragment in dystrophin R17 α1 helix. Interestingly, swapping this microdomain back into utrophin did not convey the nNOS binding activity. To identify other structural features that are required for nNOS interaction, we replaced an individual α-helix of dystrophin R16/17 with an equivalent α-helix from another dystrophin repeat. In vitro study with yeast two-hybrid suggests that most α-helices of R16/17, except for the R17 α1 helix, were dispensable for nNOS interaction. Surprisingly, in vivo binding assay showed that α2 and α3 helices of both R16 and R17 were essential for nNOS binding in muscle. We concluded that a microdomain in the α1 helix of dystrophin R17 binds to nNOS in a way uniquely defined by two pairs of the flanking helices. Our results provide an explanation for how structurally similar spectrin-like repeats in dystrophin display selective interaction with nNOS. The results also open new therapeutic avenues to restore defective nNOS homeostasis in dystrophin-null Duchenne muscular dystrophy.
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