Distinct mechanical properties in homologous spectrin-like repeats of utrophin

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number5210
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank Dr. Christopher Chamberlain and Dr. John Olthoff for assistance in generating the utrophin knockout mice used in this study. We thank Dr. Rachelle Crosbie-Watson for discussion and suggestions on utrophin function at the myotendonous junction. Supported by National Science Foundation Research Funding CMMI-1462862 to M.S. and the National Institute of Arthritis, Musculoskeletal and Skin Diseases grant RO1 AR042423 to J.M.E. J.L.M. was supported by the NIH Training Program in Muscle Research (AR007612).

Fingerprint Dive into the research topics of 'Distinct mechanical properties in homologous spectrin-like repeats of utrophin'. Together they form a unique fingerprint.

Cite this