Distinct mechanical properties in homologous spectrin-like repeats of utrophin
Autor: | Sivaraman Rajaganapathy, Murti V. Salapaka, Dawn A. Lowe, Preston M. McCourt, James M. Ervasti, Sayan Ghosal, Jackie L McCourt, Angus Lindsay |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Repetitive Sequences
Amino Acid 0301 basic medicine musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Utrophin Duchenne muscular dystrophy lcsh:Medicine macromolecular substances Microscopy Atomic Force Article Mice 03 medical and health sciences 0302 clinical medicine Protein Domains medicine Animals Spectrin lcsh:Science Multidisciplinary Sarcolemma biology Chemistry lcsh:R Cortical actin cytoskeleton medicine.disease musculoskeletal system Transmembrane protein Cell biology 030104 developmental biology biology.protein Titin lcsh:Q Dystrophin 030217 neurology & neurosurgery |
Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | Patients with Duchenne muscular dystrophy (DMD) lack the protein dystrophin, which is a critical molecular component of the dystrophin-glycoprotein complex (DGC). Dystrophin is hypothesized to function as a molecular shock absorber that mechanically stabilizes the sarcolemma of striated muscle through interaction with the cortical actin cytoskeleton via its N-terminal half and with the transmembrane protein β-dystroglycan via its C-terminal region. Utrophin is a fetal homologue of dystrophin that can subserve many dystrophin functions and is therefore under active investigation as a dystrophin replacement therapy for DMD. Here, we report the first mechanical characterization of utrophin using atomic force microscopy (AFM). Our data indicate that the mechanical properties of spectrin-like repeats in utrophin are more in line with the PEVK and Ig-like repeats of titin rather than those reported for repeats in spectrin or dystrophin. Moreover, we measured markedly different unfolding characteristics for spectrin repeats within the N-terminal actin-binding half of utrophin compared to those in the C-terminal dystroglycan-binding half, even though they exhibit identical thermal denaturation profiles. Our results demonstrate dramatic differences in the mechanical properties of structurally homologous utrophin constructs and suggest that utrophin may function as a stiff elastic element in series with titin at the myotendinous junction. |
Databáze: | OpenAIRE |
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