Distinct mechanical properties in homologous spectrin-like repeats of utrophin

Rajaganapathy, Sivaraman; McCourt, Jackie L; Ghosal, S.; Lindsay, Angus; McCourt, Preston M.; Lowe, Dawn A.; Ervasti, James M.; Salapaka, Murti V.

doi:10.1038/s41598-019-41569-4

Cited by 9 publications

(13 citation statements)

References 40 publications

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“…This interdomain structural arrangement is a signature feature of Gram-positive pilins, which could be indicative of a widespread biomechanical strategy in this bacterial group. The role of proteins as mechanical buffers or shock-absorbers has been suggested not only for bacterial adhesion structures 68,69 or tenascin 64 , but also for proteins such as utrophin 70 , dystrophin 71 , or α-actinin 1 72 , which indicates that this nanomechanical property could be widespread among proteins with mechanical roles.…”

Section: Discussionmentioning

confidence: 99%

Magnetic tweezers meets AFM: ultra-stable protein dynamics across the force spectrum

Alonso-Caballero

Tapia‐Rojo

Badilla

et al. 2021

Preprint

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Proteins that operate under force—cell adhesion, mechanosensing—exhibit a wide range of mechanostabilities. Single-molecule magnetic tweezers has enabled the exploration of the dynamics under force of these proteins with subpiconewton resolution and unbeatable stability in the 0.1-120 pN range. However, proteins featuring a high mechanostability (>120 pN) have remained elusive with this technique and have been addressed with Atomic Force Microscopy (AFM), which can reach higher forces but displays less stability and resolution. Herein, we develop a magnetic tweezers approach that can apply AFM-like mechanical loads while maintaining its hallmark resolution and stability in a range of forces that spans from 1 to 500 pN. We demonstrate our approach by exploring the folding and unfolding dynamics of the highly mechanostable adhesive protein FimA from the Gram-positive pathogen Actinomyces oris. FimA unfolds at loads >300 pN, while its folding occurs at forces <15 pN, producing a large dissipation of energy that could be crucial for the shock absorption of mechanical challenges during host invasion. Our novel magnetic tweezers approach entails an all-in-one force spectroscopy technique for protein dynamics studies across a broad spectrum of physiologically-relevant forces and timescales.

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Section: Discussionmentioning

confidence: 99%

Magnetic tweezers meets AFM: ultra-stable protein dynamics across the force spectrum

Alonso-Caballero

Tapia‐Rojo

Badilla

et al. 2021

Preprint

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“…Both proteins differ in their lateral interactions with actin [ 20 ] (Figure 2B ), utrophin containing fewer spectrin‐like repeats, and sharing only a 35% homology in the central domain with dystrophin. Moreover, a significant difference in the mechanical behaviour between spectrin repeats has been recently demonstrated [ 25 ]. Crucially, they also differ in their capacity to recruit neuronal nitric oxide synthase (nNOS), which cannot be recruited by utrophin [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies

Soblechero-Martín

López-Martínez

Puente-Ovejero

et al. 2021

Neuropathology Appl Neurobio

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Utrophin is an autosomal paralogue of dystrophin, a protein whose deficit causes Duchenne and Becker muscular dystrophies (DMD/BMD). Utrophin is naturally overexpressed at the sarcolemma of mature dystrophin‐deficient fibres in DMD and BMD patients as well as in the mdx Duchenne mouse model. Dystrophin and utrophin can co‐localise in human foetal muscle, in the dystrophin‐competent fibres from DMD/BMD carriers, and revertant fibre clusters in biopsies from DMD patients. These findings suggest that utrophin overexpression could act as a surrogate, compensating for the lack of dystrophin, and, as such, it could be used in combination with dystrophin restoration therapies. Different strategies to overexpress utrophin are currently under investigation. In recent years, many compounds have been reported to modulate utrophin expression efficiently in preclinical studies and ameliorate the dystrophic phenotype in animal models of the disease. In this manuscript, we discuss the current knowledge on utrophin protein and the different mechanisms that modulate its expression in skeletal muscle. We also include a comprehensive review of compounds proposed as utrophin regulators and, as such, potential therapeutic candidates for these muscular dystrophies.

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“…Utrophin spectrin repeats unfold at higher forces similar to that of titin rather than dystrophin 65 . This is consistent with its localisation and role for stiff elastic force transduction at the myotendinous junction but may render utrophin less suitable to act as a molecular spring in the buffering of contraction-induced forces 65 . Together, these data would suggest that there may be altered mechanotransduction and mechanical buffering capacity in the instance of utrophin overexpression, especially in light of differential binding partners/mechanisms, however, this requires further experimental examination.…”

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confidence: 99%

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confidence: 99%

“…Biomechanically, the spectrin repeats of utrophin have a distinct unfolding pattern compared to dystrophin 65 . Utrophin spectrin repeats unfold at higher forces similar to that of titin rather than dystrophin 65 . This is consistent with its localisation and role for stiff elastic force transduction at the myotendinous junction but may render utrophin less suitable to act as a molecular spring in the buffering of contraction-induced forces 65 .…”

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The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

2022

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Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the extracellular matrix (ECM). Severing the link between the ECM and the intracellular cytoskeleton has a devastating impact on the homeostasis of skeletal muscle cells, leading to a range of muscular dystrophies. In addition, the loss of a functional DGC leads to progressive dilated cardiomyopathy and premature death. Dystrophin functions as a molecular spring and the DGC plays a critical role in maintaining the integrity of the sarcolemma. Additionally, evidence is accumulating, linking the DGC to mechanosignalling, albeit this role is still less understood. This review article aims at providing an up-to-date perspective on the DGC and its role in mechanotransduction. We first discuss the intricate relationship between muscle cell mechanics and function, before examining the recent research for a role of the dystrophin glycoprotein complex in mechanotransduction and maintaining the biomechanical integrity of muscle cells. Finally, we review the current literature to map out how DGC signalling intersects with mechanical signalling pathways to highlight potential future points of intervention, especially with a focus on cardiomyopathies.

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Distinct mechanical properties in homologous spectrin-like repeats of utrophin

Cited by 9 publications

References 40 publications

Magnetic tweezers meets AFM: ultra-stable protein dynamics across the force spectrum

Magnetic tweezers meets AFM: ultra-stable protein dynamics across the force spectrum

Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies

The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

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