Functional analysis of the strategic role of Ig-like domain 24 of filamin C

• Applicants: Professor Dr. Dieter O. Fürst; Professor Dr. Rolf Schröder
• Subject Area: Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506117843

Filamin C (FLNc) is a large cytoskeletal protein directly binding to F-actin and a plethora of cellular proteins of great functional diversity, indicating that it serves as a multifunctional adapter protein. The pivotal role of FLNc in striated muscle tissue is highlighted by the observation that mutations of the human FLNC gene cause a clinically diverse group of familial and sporadic myopathies and cardiomyopathies. The actin filament-crosslinking activity of FLNc is based on dimer formation, which is mediated by its Ig-like domain 24. Moreover, this very C-terminal domain of FLNc, which contains at least four phosphorylation sites responsive to mechanical stress, is also involved in interactions with small GTPases, sarcoglycans and HSPB7. To address the functional role of this strategic domain at the cellular, molecular and tissue level in detail, we newly generated FLNc exon 47-48-specific knock-out mice lacking the Ig-like domain 24 in striated muscle tissue as well as full length FLNc cDNA constructs containing phosphosite mutants, as well as a cDNA lacking Ig-like domain 24. Using a multi-method approach, we will address the following key questions: i) How does the lack of Ig-like domain 24 of FLNc impact the structure and function of skeletal and cardiac muscle tissues under mechanical stress? ii) Does the lack of Ig-like domain 24 of FLNc impair the FLNc interactome, with special emphasis on cell signaling, the protein homeostasis machinery and cytoskeleton-associated attachment sites? iii) What is the molecular and cellular impact of site-specific phosphorylations in Ig-like domain 24? iv) Direct analysis of mechanosensitive properties of FLNc in living cells. This project will provide new and deeper insights into the functional role of FLNc and its Ig-like domain 24 in the context of cell signaling, mechanosensing and –protection, as well as protein homeostasis in normal and diseased striated muscle.

• DFG Programme: Research Grants