Journal article
Filamin C dimerisation is regulated by HSPB7
- Abstract:
- The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC is a multi-functional protein that interacts with a variety of partners, however, how it is regulated at the molecular level is not well understood. Here we investigate its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We find that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we solve by X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work therefore shows, structurally, how HSPB7 acts as a specific molecular chaperone that regulates FLNC dimerisation.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 3.9MB, Terms of use)
-
(Preview, Supplementary materials, pdf, 4.1MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41467-025-58889-x
Authors
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 201543/B/16/Z
+ Leverhulme Trust
More from this funder
- Funder identifier:
- https://ror.org/012mzw131
- Grant:
- RPG-2021-246
+ British Heart Foundation
More from this funder
- Funder identifier:
- https://ror.org/02wdwnk04
- Grant:
- FS/12/40/29712
- AA/18/2/34218
- IA/F/23/275037
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V009540/1
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 16
- Issue:
- 1
- Article number:
- 4090
- Publication date:
- 2025-05-01
- Acceptance date:
- 2025-04-02
- DOI:
- EISSN:
-
2041-1723
- ISSN:
-
2041-1723
- Language:
-
English
- Pubs id:
-
2118135
- Local pid:
-
pubs:2118135
- Deposit date:
-
2025-04-14
- ARK identifier:
Terms of use
- Copyright holder:
- Wang et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record