Duchenne muscular dystrophy (DMD) gene encodes dystrophin, a large multidomain protein. Its nonfunctionality leads to dystrophinopathies like DMD and Becker muscular dystrophy, for which no cure is yet available. A few therapies targeted towards specific mutations can extend the lifespan of patients, although with limited efficacy and high costs, emphasizing the need for more general treatments. Dystrophin's complex structure with poorly understood domains and the presence of multiple isoforms with varied expression patterns in different tissues pose challenges in therapeutic development. The C-terminal (CT) domain of dystrophin is less understood in terms of its structure-function, although it has been shown to perform important functional roles by interacting with another cytosolic protein, dystrobrevin. Dystrophin and dystrobrevin stabilize the sarcolemma membrane by forming a multiprotein complex called dystrophin-associated glycoprotein complex that is destabilized in DMD. Dystrobrevin has two major isoforms, alpha and beta, with tissue-specific expression patterns. Here, we characterize the CT domain of dystrophin and its interactions with the two dystrobrevin isoforms. We show that the CT domain is nonglobular and shows reversible urea denaturation as well as thermal denaturation. It interacts with dystrobrevin isoforms differentially, with differences in binding affinity and the mode of interaction. We further show that the amino acid differences in the CT region of dystrobrevin isoforms contribute to these differences. These results have implications for the stability of dystrophin-associated glycoprotein complex in different tissues and explain the differing symptoms associated with DMD patients affecting organs beyond the skeletal muscles.
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http://dx.doi.org/10.1016/j.jbc.2024.108002 | DOI Listing |
J Biol Chem
November 2024
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address:
Duchenne muscular dystrophy (DMD) gene encodes dystrophin, a large multidomain protein. Its nonfunctionality leads to dystrophinopathies like DMD and Becker muscular dystrophy, for which no cure is yet available. A few therapies targeted towards specific mutations can extend the lifespan of patients, although with limited efficacy and high costs, emphasizing the need for more general treatments.
View Article and Find Full Text PDFPsychiatr Danub
July 2023
Department of Biotechnology, University of Rijeka, Rijeka, Croatia.
Background: It has been proposed that aggregation of specific proteins in the brain may be a pathological element in schizophrenia and other chronic disorders. Multiple such aggregating proteins have now been implicated through post mortem investigation, including NPAS3 (Neuronal PAS domain protein 3), dysbindin-1 (encoded by the DTNBP1, Dystrobrevin Binding Protein 1, gene) and TRIOBP (Trio-Binding Protein, multiple isoforms). While the presence of protein aggregates in the brain is interesting in terms of understanding pathology, it is impractical as a biomarker.
View Article and Find Full Text PDFProteomes
February 2021
Department of Biology, Maynooth University, National University of Ireland, W23F2H6 Maynooth, Co. Kildare, Ireland.
The systematic bioanalytical characterization of the protein product of the gene, which is defective in the pediatric disorder Duchenne muscular dystrophy, led to the discovery of the membrane cytoskeletal protein dystrophin. Its full-length muscle isoform Dp427-M is tightly linked to a sarcolemma-associated complex consisting of dystroglycans, sarcoglyans, sarcospan, dystrobrevins and syntrophins. Besides these core members of the dystrophin-glycoprotein complex, the wider dystrophin-associated network includes key proteins belonging to the intracellular cytoskeleton and microtubular assembly, the basal lamina and extracellular matrix, various plasma membrane proteins and cytosolic components.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Basis Dis
January 2021
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Electronic address:
The molecular and cellular basis for cataract development in mice lacking dystrophin, a scaffolding protein that links the cytoskeleton to the extracellular matrix, is poorly understood. In this study, we characterized lenses derived from the dystrophin-deficient mdx mouse model. Expression of Dp71, a predominant isoform of dystrophin in the lens, was induced during lens fiber cell differentiation.
View Article and Find Full Text PDFFront Neurosci
August 2020
Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.
Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease caused by defective expression of the cytoskeletal protein dystrophin (Dp427). Selected autonomic and central neurons, including retinal neurons, express Dp427 and/or dystrophin shorter isoforms. Because of this, DMD patients may also experience different forms of cognitive impairment, neurological and autonomic disorders, and specific visual defects.
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