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 journalArticle

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

Fingerprint

Utrophin
Spectrin
Dystrophin
Dystroglycans
Connectin
Duchenne Muscular Dystrophy
Sarcolemma
Striated Muscle
Atomic Force Microscopy
Actin Cytoskeleton
Actins
Glycoproteins
Proteins
Hot Temperature

PubMed: MeSH publication types

  • Journal Article

Cite this

Distinct mechanical properties in homologous spectrin-like repeats of utrophin. / Rajaganapathy, Sivaraman; McCourt, Jackie L.; Ghosal, Sayan; Lindsay, Angus; McCourt, Preston M.; Lowe, Dawn A; Ervasti, James M; salapaka, murti v.

In: Scientific reports, Vol. 9, No. 1, 5210, 01.12.2019.

Research output: Contribution to journalArticle

Rajaganapathy, Sivaraman ; McCourt, Jackie L. ; Ghosal, Sayan ; Lindsay, Angus ; McCourt, Preston M. ; Lowe, Dawn A ; Ervasti, James M ; salapaka, murti v. / Distinct mechanical properties in homologous spectrin-like repeats of utrophin. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{46dc724b959d4f85bd9fd43fd75ef3b7,
title = "Distinct mechanical properties in homologous spectrin-like repeats of utrophin",
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.",
author = "Sivaraman Rajaganapathy and McCourt, {Jackie L.} and Sayan Ghosal and Angus Lindsay and McCourt, {Preston M.} and Lowe, {Dawn A} and Ervasti, {James M} and salapaka, {murti v}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-41569-4",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Distinct mechanical properties in homologous spectrin-like repeats of utrophin

AU - Rajaganapathy, Sivaraman

AU - McCourt, Jackie L.

AU - Ghosal, Sayan

AU - Lindsay, Angus

AU - McCourt, Preston M.

AU - Lowe, Dawn A

AU - Ervasti, James M

AU - salapaka, murti v

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063493267&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063493267&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-41569-4

DO - 10.1038/s41598-019-41569-4

M3 - Article

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 5210

ER -