Journal article
Structure and assembly of the dystrophin glycoprotein complex
Nature (London), Vol.637(8048), pp.1252-1260
01/30/2025
DOI: 10.1038/s41586-024-08310-2
PMCID: PMC13178787
PMID: 39663450
Abstract
The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix
. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration
. Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed
. On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin-dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.
Details
- Title: Subtitle
- Structure and assembly of the dystrophin glycoprotein complex
- Creators
- Li Wan - Westlake UniversityXiaofei Ge - Tsinghua UniversityQikui Xu - Westlake UniversityGaoxingyu Huang - Westlake UniversityTiandi Yang - Harvard Medical SchoolKevin P Campbell - Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USAZhen Yan - Institute for Advanced StudyJianping Wu - Westlake University
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.637(8048), pp.1252-1260
- DOI
- 10.1038/s41586-024-08310-2
- PMID
- 39663450
- PMCID
- PMC13178787
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- NATURE PORTFOLIO
- Grant note
- National Natural Science Foundation of China: 32271261, 32271239 Zhejiang Provincial Natural Science Foundation of China: LR22C050003, 1011103860222B1, 1011103560222B1, 101486021901, 101456021901 National Institute of Neurological Disorders and Stroke of the National Institutes of Health: P50NS053672
The authors thank the cryo-EM Facility of Westlake University for providing support on cryo-EM data collection; Westlake University HPC Center for computational resources and related assistance; the Mass Spectrometry and Metabolomics Core Facility of Westlake University for mass spectrometry analysis. This work was supported by National Natural Science Foundation of China (32271261 to J.W. and 32271239 to Z.Y.), Zhejiang Provincial Natural Science Foundation of China (LR22C050003 to J.W.), Westlake University (1011103860222B1 to J.W. and 1011103560222B1 to Z.Y.) and Westlake Education Foundation (101486021901 to J.W. and 101456021901 to Z.Y.). Research reported in this publication was also supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number P50NS053672 to K.P.C. K.P.C is an investigator of the Howard Hughes Medical Institute.
- Language
- English
- Electronic publication date
- 12/11/2024
- Date published
- 01/30/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984757682702771
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