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Actomyosin forces trigger a conformational change in desmoplakin within desmosomes
Open accessPreprint — published as 10.1038/s41467-025-64124-4 · Paper page
Abstract
Desmosomes are essential cell-cell adhesion organelles that enable tension-prone tissue, like the skin and heart, to withstand mechanical stress. Desmosomal anomalies are associated with numerous epidermal disorders and cardiomyopathies. Despite their critical role in maintaining tissue resilience, an understanding of how desmosomes sense and respond to mechanical stimuli is lacking. Here, we use a combination of super-resolution imaging, FRET-based tension sensors, atomistic computer simulations, and biochemical assays to demonstrate that actomyosin forces induce a conformational change in desmoplakin, a critical cytoplasmic desmosomal protein. We show that in human breast cancer MCF7 cells, actomyosin contractility reorients keratin intermediate filaments and directs force to desmoplakin along the keratin filament backbone. These forces induce a conformational change in the N-terminal plakin domain of desmoplakin, converting this domain from a folded (closed) to an extended (open) conformation. Our findings establish that desmoplakin is mechanosensitive and responds to changes in cellular load by undergoing a force-induced conformational change.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Dong, Y., Elgerbi, A., Xie, B., Choy, J. S., & Sivasankar, S.
- Affiliations
- University of California, Davis (US)
- Catholic University of America (US)
- Corresponding author
- Sivasankar, Sanjeevi
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2024-11-21
- Volume
- 16
- Issue
- 1
- Pages
- 9052-9052
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12514153
- OpenAlex
- W4415049906
- Cited by
- 10
- References
- 1
- Citations by year
- 2026: 6 · 2025: 4
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health and Human Services (R01HL127711, R15CA267890-01, R01GM121885)
- National Institutes of Health (1r15ca267890-01)
- University of California, Davis (P30CA093373, NCI P30CA093373)
- National Heart, Lung, and Blood Institute (R01HL127711, HL127711)
- National Cancer Institute (R15 CA267890, NCI P30 CA093373, R15CA267890-01, P30CA093373)
- National Institute of General Medical Sciences (R01GM121885)
- Comprehensive Cancer Center, University of California, Davis (NCI P30CA093373, P30CA093373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- desmoplakin, desmosomes, actomyosin contractility, mechanosensing, protein conformational change, keratin 19, keratin intermediate filaments, cardiomyocytes, MCF-7 cells, cell-cell adhesion
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