Abstract
Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.
Highlights
Filamin C (FLNC) protein is one of three filamin isoforms (A, B, C) that cross-link actin filaments (F-actin) and interact with various binding partners [1,2]
Filamin A (FLNA) and Filamin B (FLNB) are concentrated in vascular endothelial cells [10,12], low expression of FLNB is detected in skeletal muscle
The atomic structure of FLNC spectrin related actin-binding domain (srABD) is not available, its sequence similarity to the srABD of FLNA and B is over 90%
Summary
Filamin C (FLNC) protein is one of three filamin isoforms (A, B, C) that cross-link actin filaments (F-actin) and interact with various binding partners [1,2]. Loss of hinge-1 and insertion of 82 amino acids in R20 of FLNC would influence the structure of full-length FLNC molecule but purified FLNC molecule is currently not available to investigate Such a unique structure of FLNC, if any, could determine the function of FLNC in muscle Z-disc. The last repeat, R24, of FLNA is sufficient to form an L-shaped homodimer [27], but biochemical and yeast two hybrid analysis demonstrated that heterodimerization between different filamin isoforms is possible [32,33] This could be a reason why FLNB occasionally localized at the Z-discs in cultured C2C12 myoblasts by forming a heterodimer with FLNC [22]. It is possible that dimerization or even oligomerization of filamin subunits are mediated by their binding partners which are dimerized or oligomerized [34]
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