The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and α-actinin

Linnemann, Anja; Ven, Peter F.M. van der; Vakeel, Padmanabhan; Albinus, Britta; Simonis, Dirk; Bendas, Gerd; Schenk, Jörg A.; Micheel, Burkhard; Kley, Rudolf A.; Fürst, Dieter O.

doi:10.1016/j.ejcb.2010.04.004

Cited by 65 publications

(71 citation statements)

References 65 publications

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“…This is consistent with ultrastructural studies that showed myofibrillar alterations mainly at the Z-disc level (4,6). But even within the increasing list of Z-disc-associated proteins only a defined subset was consistently revealed: the known FLNc-interacting proteins N-RAP, obscurin and myotilin (19,31,36 and unpublished data) were enriched in aggregates, whereas ␣-actinin and its direct interactors such as myopodin (29,37), were neither detected in aggregates by our proteomic approach, nor by immunofluorescence studies (unpublished data). This supports our proposal that the Z-disc contains two sets of proteins: one that is more strongly bound to FLNc and is prone to be involved in MFM, and a second group of proteins more firmly associated with ␣-actinin, probably involved in other myopathies (26).…”

Section: Fig 1 Workflow For the Identification Of Mfm Biomarkers Bysupporting

confidence: 72%

“…The construct encoding the T7-tagged carboxyterminus of Xin encodes amino acids 1686 -1812 (Uniprot Q702N8 -1). Protein expression in, and purification from E. coli BL21(DE3)Codon Plus cells (Stratagene, La Jolla, CA) was performed as described previously (29). Inverse PCR was used to delete the cDNA encoding the FLNc-specific insertion from Ig-like domain 20.…”

Section: Validation Of Proteomic Findings Bymentioning

confidence: 99%

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A Combined Laser Microdissection and Mass Spectrometry Approach Reveals New Disease Relevant Proteins Accumulating in Aggregates of Filaminopathy Patients

Kley

Maerkens

Leber

et al. 2013

Molecular & Cellular Proteomics

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Filaminopathy is a subtype of myofibrillar myopathy caused by mutations in FLNC, the gene encoding filamin C, and histologically characterized by pathologic accumulation of several proteins within skeletal muscle fibers. With the aim to get new insights in aggregate composition, we collected aggregates and control tissue from skeletal muscle biopsies of six myofibrillar myopathy patients harboring three different FLNC mutations by laser microdissection and analyzed the samples by a label-free mass spectrometry approach. A total of 390 proteins were identified, and 31 of those showed significantly higher spectral indices in aggregates compared with patient controls with a ratio >1.8. These proteins included filamin C, other known myofibrillar myopathy associated proteins, and a striking number of filamin C binding partners. Across the patients the patterns were extremely homogeneous. Xin actin-binding repeat containing protein 2, heat shock protein 27, nebulin-related-anchoring protein, and Rab35 could be verified as new filaminopathy biomarker candidates. In addition, further experiments identified heat shock protein 27 and Xin actin-binding repeat containing protein 2 as novel filamin C interaction partners and we could show that Xin actin-binding repeat containing protein 2 and the known interaction partner Xin actinbinding repeat containing protein 1 simultaneously associate with filamin C. Ten proteins showed significant lower spectral indices in aggregate samples compared with patient controls (ratio <0.56) including M-band proteins myomesin-1 and myomesin-2. Proteomic findings were consistent with previous and novel immunolocalization data. Our findings suggest that aggregates in filaminopathy have a largely organized structure of proteins also interacting under physiological conditions. Different filamin C mutations seem to lead to almost identical aggregate compositions. The finding that filamin C was detected as highly abundant protein in aggregates in filaminopathy indicates that our proteomic approach may be suitable to identify new candidate genes among the many MFM patients with so far unknown mutation. Molecular & Cellular Proteomics

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Section: Fig 1 Workflow For the Identification Of Mfm Biomarkers Bysupporting

confidence: 72%

Section: Validation Of Proteomic Findings Bymentioning

confidence: 99%

A Combined Laser Microdissection and Mass Spectrometry Approach Reveals New Disease Relevant Proteins Accumulating in Aggregates of Filaminopathy Patients

Kley

Maerkens

Leber

et al. 2013

Molecular & Cellular Proteomics

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“…Phosphorylation via PKA and Ca 2ϩ /calmodulin-dependent protein kinase II promotes nuclear import, whereas dephosphorylation by calcineurin abrogates 14-3-3 binding and supports myopodin binding to ␣-actinin (95). Although its biological function is still undefined, recent findings support a role for myopodin as a z-disc multiadaptor protein (96).…”

Section: Shuttling Z-disc Moleculesmentioning

confidence: 91%

Cardiac Z-disc Signaling Network

Frank

Frey

2011

Journal of Biological Chemistry

156

139

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During the last 15 years, the perception of the cardiac z-disc has undergone substantial changes. Initially viewed as a structural component at the lateral boundaries of the sarcomere, the cardiac z-disc has increasingly become recognized as a nodal point in cardiomyocyte signal transduction and disease. This minireview thus focuses on novel components and recent developments in z-disc biology and their role in cardiac signaling and disease.

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“…It has been shown that filamin C interacts with two major protein complexes at the sarcolemma, namely the dystrophin-associated glycoprotein complex (DGC) (Thompson et al, 2000) and the integrin complex (Gontier et al, 2005;Loo et al, 1998), both of which are known to have important roles in affording mechanical integrity to striated muscle. However, through its C-terminal region, filamin C also binds the Z-band proteins myotilin (van der Ven et al, 2000b) and myopodin (synaptopodin 2) (Linnemann et al, 2010), suggesting that it ensures a link between Z-bands and sarcolemmal DGC and integrin complexes, thus maintaining the mechanical integrity of muscle cells. This possibility is supported by the detachment of myofibrils from sarcolemma and intercalated Z-bands in muscles of zacro (filamin C) medaka mutants (Fujita et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Drosophila small heat shock protein CryAB ensures structural integrity of developing muscles, and proper muscle and heart performance

et al. 2015

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Molecular chaperones, such as the small heat shock proteins (sHsps), maintain normal cellular function by controlling protein homeostasis in stress conditions. However, sHsps are not only activated in response to environmental insults, but also exert developmental and tissuespecific functions that are much less known. Here, we show that during normal development the Drosophila sHsp CryAB [L(2)efl] is specifically expressed in larval body wall muscles and accumulates at the level of Z-bands and around myonuclei. CryAB features a conserved actin-binding domain and, when attenuated, leads to clustering of myonuclei and an altered pattern of sarcomeric actin and the Z-band-associated actin crosslinker Cheerio (filamin). Our data suggest that CryAB and Cheerio form a complex essential for muscle integrity: CryAB colocalizes with Cheerio and, as revealed by mass spectrometry and co-immunoprecipitation experiments, binds to Cheerio, and the muscle-specific attenuation of cheerio leads to CryAB-like sarcomeric phenotypes. Furthermore, muscle-targeted expression of CryAB R120G , which carries a mutation associated with desmin-related myopathy (DRM), results in an altered sarcomeric actin pattern, in affected myofibrillar integrity and in Z-band breaks, leading to reduced muscle performance and to marked cardiac arrhythmia. Taken together, we demonstrate that CryAB ensures myofibrillar integrity in Drosophila muscles during development and propose that it does so by interacting with the actin crosslinker Cheerio. The evidence that a DRM-causing mutation affects CryAB muscle function and leads to DRM-like phenotypes in the fly reveals a conserved stress-independent role of CryAB in maintaining muscle cell cytoarchitecture.

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The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and α-actinin

Cited by 65 publications

References 65 publications

A Combined Laser Microdissection and Mass Spectrometry Approach Reveals New Disease Relevant Proteins Accumulating in Aggregates of Filaminopathy Patients

A Combined Laser Microdissection and Mass Spectrometry Approach Reveals New Disease Relevant Proteins Accumulating in Aggregates of Filaminopathy Patients

Cardiac Z-disc Signaling Network

Drosophila small heat shock protein CryAB ensures structural integrity of developing muscles, and proper muscle and heart performance

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