Abstract:Filamins are multi-domain, actin cross-linking, and scaffolding proteins. In addition to the actin cross-linking function, filamins have a role in mechanosensor signaling. The mechanosensor function is mediated by domain-domain interaction in the C-terminal region of filamins. Recently, we have shown that there is a three-domain interaction module in the N-terminal region of filamins, where the neighboring domains stabilize the structure of the middle domain and thereby regulate its interaction with ligands. I… Show more
“…3b). A similar distribution was observed for the semi-extended Ig domain pair 6–7 of filamin C 49 . Taken together, these results reveal that tandem Ig domains of myotilin display a certain degree of flexibility and exist in different relative orientations, most likely due to the flexible nature of the linker between the two domains.Figure 3Flexibility assessment of the tandem Ig domains.…”
Section: Resultssupporting
confidence: 78%
“…Other parameters derived from scattering data are given in Table 1. D max and R g values of MYOTIg1–2 are between those of a fully extended Ig8–9 pair (D max = 10.10 nm) and semi-extended Ig6–7 pair of filamin C (D max = 8.60 nm) 49 , suggesting that the MYOTIg1–2 pair adopts a slightly more compact form than the fully extended Ig8–9.Figure 2SAXS analysis of myotilin Ig domains. ( a ) P(r) vs .…”
Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism.
“…3b). A similar distribution was observed for the semi-extended Ig domain pair 6–7 of filamin C 49 . Taken together, these results reveal that tandem Ig domains of myotilin display a certain degree of flexibility and exist in different relative orientations, most likely due to the flexible nature of the linker between the two domains.Figure 3Flexibility assessment of the tandem Ig domains.…”
Section: Resultssupporting
confidence: 78%
“…Other parameters derived from scattering data are given in Table 1. D max and R g values of MYOTIg1–2 are between those of a fully extended Ig8–9 pair (D max = 10.10 nm) and semi-extended Ig6–7 pair of filamin C (D max = 8.60 nm) 49 , suggesting that the MYOTIg1–2 pair adopts a slightly more compact form than the fully extended Ig8–9.Figure 2SAXS analysis of myotilin Ig domains. ( a ) P(r) vs .…”
Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism.
“…Filamin C is a dimeric actin-cross-linking protein highly expressed in both skeletal and cardiac muscle, localized to the sarcolemma, Z-disk, and myotendinous junctions, and is associated with structural stability, mechanosensation, and intracellular signaling [21][22][23] . Recently, filamin C was also shown to mediate fast repair of myofibrillar microdamage in cardiomyocytes, in addition to Z-disk assembly [24] .…”
Section: Discussionmentioning
confidence: 99%
“…The mutation described here, c.4636G>A G1546S, is located in the 14th Ig-like domain, which is thought to dimerize with the 15th domain just before the hinge region. Interference in the ability of these two domains to dimerize has been hypothesized to destabilize protein folding of the entire filamin C protein [22] . As a highly dynamic protein which interacts with many substrates, missense alterations in FLNC could feasibly destabilize interactions with other proteins and alter cytoplasmic distribution in cardiomyocytes [17,30,31] .…”
Aim: Idiopathic cardiomyopathy is often genetic in origin, typically autosomal dominant, and restrictive cardiomyopathy (RCM) is the rarest form. Clinically, RCM prognosis is poor with most patients requiring heart transplant due to impaired diastolic function leading to heart failure. In some cases, desminopathy is also observed, whereby desmin protein aggregates in the myocardium. Many genes are known to be involved in cardiomyopathy, and we sought to find the pathogenic mutation of a four-generation family with RCM and desminopathy.
Methods:We employed whole exome sequence analysis of four RCM patients from the family, to identify the underlying pathogenic mutation(s).Results: Analysis of the exome data led to identification of two putative pathogenic variants. One, a nonsense mutation in ADD3, encoding adducin 3, was found in the proband and his affected daughter, but not other family members. The other was a missense mutation (G1546S) in the gene encoding filamin C (FLNC), found in all of the affected individuals. Both of these proteins interact with proteins involved in sarcomere function, and are expressed in both heart and skeletal muscle. FLNC has recently been implicated as a cardiomyopathy gene, but ADD3 has not at this point.
Conclusion:We present bioinformatic analyses that suggest that the FLNC variant is the major pathogenic variant affecting this family, but cannot rule out some contribution of the ADD3 mutation in at least two patients.
“…Although the repeats were predicted to be linearly aligned to form rods (rod-1, R1-R15; rod-2, R16-R23, Figure 2) based on the V-shaped structure of the purified FLNA molecule [25], structural analysis of the shorter fragments of the rods revealed domain-domain pairs in R3-R5, R16-R17, R18-R19, and R20-R21 [26][27][28][29] (Figure 2). Small-angle X-ray scattering revealed a compact structure in FLNC R3-R5 and possibly in R11-R12 and R14-R15 [29,30]. These domain pairs can be unfolded by mechanical forces to expose cryptic binding site as discussed below (mechanotransduction).…”
Section: Structure Of Filamin C (Flnc) and Its Family Proteinsmentioning
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.
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