Cargando…
Mechanical stability of αT-catenin and its activation by force for vinculin binding
αT (Testes)-catenin, a critical factor regulating cell–cell adhesion in the heart, directly couples the cadherin-catenin complex to the actin cytoskeleton at the intercalated disk (ICD), a unique cell–cell junction that couples cardiomyocytes. Loss of αT-catenin in mice reduces plakophilin2 and conn...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727763/ https://www.ncbi.nlm.nih.gov/pubmed/31318313 http://dx.doi.org/10.1091/mbc.E19-02-0102 |
_version_ | 1783449319987216384 |
---|---|
author | Pang, Si Ming Le, Shimin Kwiatkowski, Adam V. Yan, Jie |
author_facet | Pang, Si Ming Le, Shimin Kwiatkowski, Adam V. Yan, Jie |
author_sort | Pang, Si Ming |
collection | PubMed |
description | αT (Testes)-catenin, a critical factor regulating cell–cell adhesion in the heart, directly couples the cadherin-catenin complex to the actin cytoskeleton at the intercalated disk (ICD), a unique cell–cell junction that couples cardiomyocytes. Loss of αT-catenin in mice reduces plakophilin2 and connexin 43 recruitment to the ICD. Since αT-catenin is subjected to mechanical stretch during actomyosin contraction in cardiomyocytes, its activity could be regulated by mechanical force. To provide insight in how force regulates αT-catenin function, we investigated the mechanical stability of the putative, force-sensing middle (M) domain of αT-catenin and determined how force impacts vinculin binding to αT-catenin. We show that 1) physiological levels of force, <15 pN, are sufficient to unfold the three M domains; 2) the M1 domain that harbors the vinculin-binding site is unfolded at ∼6 pN; and 3) unfolding of the M1 domain is necessary for high-affinity vinculin binding. In addition, we quantified the binding kinetics and affinity of vinculin to the mechanically exposed binding site in M1 and observed that αT-catenin binds vinculin with low nanomolar affinity. These results provide important new insights into the mechanosensing properties of αT-catenin and how αT-catenin regulates cell–cell adhesion at the cardiomyocyte ICD. |
format | Online Article Text |
id | pubmed-6727763 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-67277632019-10-07 Mechanical stability of αT-catenin and its activation by force for vinculin binding Pang, Si Ming Le, Shimin Kwiatkowski, Adam V. Yan, Jie Mol Biol Cell Articles αT (Testes)-catenin, a critical factor regulating cell–cell adhesion in the heart, directly couples the cadherin-catenin complex to the actin cytoskeleton at the intercalated disk (ICD), a unique cell–cell junction that couples cardiomyocytes. Loss of αT-catenin in mice reduces plakophilin2 and connexin 43 recruitment to the ICD. Since αT-catenin is subjected to mechanical stretch during actomyosin contraction in cardiomyocytes, its activity could be regulated by mechanical force. To provide insight in how force regulates αT-catenin function, we investigated the mechanical stability of the putative, force-sensing middle (M) domain of αT-catenin and determined how force impacts vinculin binding to αT-catenin. We show that 1) physiological levels of force, <15 pN, are sufficient to unfold the three M domains; 2) the M1 domain that harbors the vinculin-binding site is unfolded at ∼6 pN; and 3) unfolding of the M1 domain is necessary for high-affinity vinculin binding. In addition, we quantified the binding kinetics and affinity of vinculin to the mechanically exposed binding site in M1 and observed that αT-catenin binds vinculin with low nanomolar affinity. These results provide important new insights into the mechanosensing properties of αT-catenin and how αT-catenin regulates cell–cell adhesion at the cardiomyocyte ICD. The American Society for Cell Biology 2019-07-22 /pmc/articles/PMC6727763/ /pubmed/31318313 http://dx.doi.org/10.1091/mbc.E19-02-0102 Text en © 2019 Pang, Le, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Pang, Si Ming Le, Shimin Kwiatkowski, Adam V. Yan, Jie Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title | Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title_full | Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title_fullStr | Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title_full_unstemmed | Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title_short | Mechanical stability of αT-catenin and its activation by force for vinculin binding |
title_sort | mechanical stability of αt-catenin and its activation by force for vinculin binding |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727763/ https://www.ncbi.nlm.nih.gov/pubmed/31318313 http://dx.doi.org/10.1091/mbc.E19-02-0102 |
work_keys_str_mv | AT pangsiming mechanicalstabilityofatcateninanditsactivationbyforceforvinculinbinding AT leshimin mechanicalstabilityofatcateninanditsactivationbyforceforvinculinbinding AT kwiatkowskiadamv mechanicalstabilityofatcateninanditsactivationbyforceforvinculinbinding AT yanjie mechanicalstabilityofatcateninanditsactivationbyforceforvinculinbinding |