Structure and Function of Filamin C in the Muscle Z-Disc

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.

The relationship between microbiomes and selective regimes in the sponge genusIrcinia

“…Two of the loci under positive selection (FLNC and FLNB) are involved in cellular mechanics, including the development and functioning of muscles in other metazoans [81][82][83];…”

Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies

“…In heart and muscles, FLNC localizes to Z-discs, myotendinous junctions, sarcolemma and intercalated discs [ 21 ]. Since FLNC is highly expressed in Z-discs and is structurally similar to filamin A—which has been shown to be a mechano-sensor and -transducer—it is natural to assume that filamin C is also implicated in mechanical stability, force transmission and mechanotransduction [ 22 ]. In general, filamins are key elements that crosslink actin filaments into orthogonal networks [ 23 ].…”

“…Filamin contributes to the mechanical stability of cells by linking the internal actin network with membrane receptors and mechanosensitive components. To the best of our knowledge, more than 90 different proteins—e.g., cell adhesion proteins and dystrophin-glycoprotein complex (DGC)- have been proven to interact with FLNC, but the list is being constantly broadened [ 21 , 22 ].…”

“…Filamins are naturally found in cells as elongated, V-shaped dimers that dimerize at their C-termini [ 23 ]. Filamins are formed by an N-terminal spectrin-related ABD—called the “head”—followed by 24 immunoglobulin-like repeats—called the “backbone”—and a C-terminus located at the 24th repeat [ 22 , 23 ] ( Figure 3 ).…”

“…The “head” is similar to that of alpha-actinin and dystrophin and its role is the same [ 23 ]. In the “backbone” there are two hinges, that separate R15 from R16 (hinge-1) and R23 from R24 (hinge-2) and confer more flexibility to the structure [ 22 ]. Interestingly, hinge-1 has been shown to be crucial for the mechanics of actin networks.…”