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Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice

Mokhonova, Ekaterina I. ; Helzer, Daniel ; Malik, Ravinder ; Mamsa, Hafsa ; Walker, Jackson ; Maslanka, Mark ; Fleser, Tess S. ; Afsharinia, Mohammad H. ; Liu, Shiheng and Holmberg, Johan LU , et al. (2025) In Journal of Clinical Investigation 135(17).
Abstract

The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element... (More)

The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in δ-sarcoglycanopathies, enabling substitution of δ-sarcoglycan by its homolog, ζ-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that ζ-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protects the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
135
issue
17
article number
e187868
publisher
American Society for Clinical Investigation
external identifiers
  • scopus:105015054136
  • pmid:40549548
ISSN
0021-9738
DOI
10.1172/JCI187868
language
English
LU publication?
yes
id
973820e9-a66d-4bb4-bf50-832d6bab3010
date added to LUP
2025-11-14 14:13:46
date last changed
2025-11-15 03:00:02
@article{973820e9-a66d-4bb4-bf50-832d6bab3010,
  abstract     = {{<p>The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in δ-sarcoglycanopathies, enabling substitution of δ-sarcoglycan by its homolog, ζ-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that ζ-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protects the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.</p>}},
  author       = {{Mokhonova, Ekaterina I. and Helzer, Daniel and Malik, Ravinder and Mamsa, Hafsa and Walker, Jackson and Maslanka, Mark and Fleser, Tess S. and Afsharinia, Mohammad H. and Liu, Shiheng and Holmberg, Johan and Zhou, Z. Hong and Deeds, Eric J. and Hansen, Kirk C. and McNally, Elizabeth M. and Crosbie, Rachelle H.}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  number       = {{17}},
  publisher    = {{American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice}},
  url          = {{http://dx.doi.org/10.1172/JCI187868}},
  doi          = {{10.1172/JCI187868}},
  volume       = {{135}},
  year         = {{2025}},
}