Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling

Eulitz, Stefan; Sauer, Florian; Pelissier, M.C.; Boisguérin, Prisca; Molt, Sibylle; Schuld, Julia; Orfanos, Zacharias; Kley, Rudolf A.; Volkmer, Rudolf; Wilmanns, Matthias; Kirfel, Gregor; Ven, Peter F.M. van der; Fürst, Dieter O.

doi:10.1091/mbc.e13-04-0202

Cited by 35 publications

(36 citation statements)

References 71 publications

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“…They contain several peptide motifs, which bind actin filaments by coiling around them, similar to nebulin repeats (Cherepanova et al, 2006;Pacholsky et al, 2004). Xin and XIRP interact temporally and spatially with nebulin in differentiating striated muscle cells and in areas of myofibrillar remodeling in adult muscle fibers (Eulitz et al, 2013). These data suggest that nebulin may initiate myofibrillar actin filament formation through complex formation with N-WASP and/or Xin repeat-containing proteins.…”

Section: Nebulin Has Diverse Rolesmentioning

confidence: 93%

“…The second group is associated with myofibrillogenesis, including Xin-repeatcontaining protein family members (XIRP2 and Xin) and neuronal Wiscott-Aldrich syndrome protein (N-WASP). The interaction between Xin-repeat proteins and nebulin is transient, only occurring during myofibril assembly and remodeling (Eulitz et al, 2013). The nebulin-N-WASP complex is important for actin nucleation and elongation, which is crucial for IGF-induced muscle hypertrophy (Takano et al, 2010).…”

Section: Thin Filament Tropomodulinmentioning

confidence: 99%

“…Knocking down N-WASP in mice blocked both developmental and IGF-1-induced hypertrophy (Takano et al, 2010). Additional studies have demonstrated that the Xin repeat-containing proteins Xin and XIRP2 interact with nebulin during myofibril formation and remodeling (Eulitz et al, 2013). Xins are multi-adaptor proteins mainly expressed in cardiac and skeletal muscles, and are involved in muscle development, function, regeneration and disease (Wang et al, 2014).…”

Section: Nebulin Has Diverse Rolesmentioning

confidence: 99%

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Nebulin, a multi-functional giant

Chu

Gregorio

Pappas

2016

Journal of Experimental Biology

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Efficient muscle contraction in skeletal muscle is predicated on the regulation of actin filament lengths. In one long-standing model that was prominent for decades, the giant protein nebulin was proposed to function as a 'molecular ruler' to specify the lengths of the thin filaments. This theory was questioned by many observations, including experiments in which the length of nebulin was manipulated in skeletal myocytes; this approach revealed that nebulin functions to stabilize filamentous actin, allowing thin filaments to reach mature lengths. In addition, more recent data, mostly from in vivo models and identification of new interacting partners, have provided evidence that nebulin is not merely a structural protein. Nebulin plays a role in numerous cellular processes including regulation of muscle contraction, Z-disc formation, and myofibril organization and assembly.

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Section: Nebulin Has Diverse Rolesmentioning

confidence: 93%

Section: Thin Filament Tropomodulinmentioning

confidence: 99%

Section: Nebulin Has Diverse Rolesmentioning

confidence: 99%

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Nebulin, a multi-functional giant

Chu

Gregorio

Pappas

2016

Journal of Experimental Biology

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“…65 Furthermore, ex vivo experiments on isolated adult cardioskeleton; 54,56 (3) the Zis1 and PEVK regions of titin, a giant protein stretching half a sarcomere from the Z-line to the M-line; 33,55,57 (4) zyxin, associated with focal adhesions and actin based structures, involved in cytoskeletal organization; 22 (5) neuronal Wiscott-Aldrich syndrome protein (N-WASP/ WASL), regulating actin polymerization; 53 and (6) the Xin actin-binding repeat-containing (XIRP) family members Xin and XIRP2 with which they interact transiently during development and remodeling. 58 Furthermore, both the SH3 domain and the nebulin repeats bind with high affinity to α-actinin in the Z-line. 10 Similar to observations in nebulin-deficient skeletal mouse muscle and myoblasts, 26,27,29,30,32,33 reduced endogenous nebulette levels in chick embryonic cardiomyocytes as a consequence of overexpression of the nebulette serine-rich linker region or SH3 domain, resulted in shorter thin filaments.…”

Section: Nebulettementioning

confidence: 99%

Roles of Nebulin Family Members in the Heart

Bang

Chen

2015

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp ment. 4,10,11,13-15 N-RAP is the second largest member of the nebulin family (193)(194)(195)(196) kDa in humans) containing 46 nebulin repeats of which 35 are organized into 5 super repeats, 16,17 while nebulette (109 kDa), 3,18 LASP-1 (37 kDa), 19,20 and LASP-2 (34 kDa) 21-23 contain only simple nebulin repeats. Nebulette contains up to 23 repeats, 3 while LASP-1 and LASP-2 contain only 2 and 3 repeats, respectively. Except for N-RAP the family members also share an SH3 domain at their C-terminus, and N-RAP, LASP-1, and LASP-2 contain an N-terminal LIM domain not present in nebulin or nebulette. Apart from their similar domain structure and linkage to actin, the members of the nebulin family are quite heterogeneous both with respect to molecular size (34-900 kDa) and expression pattern as well as function, which includes roles in stabilization and scaffolding of cytoskeletal structures, cell migration, and organization of the actin cytoskeleton. In the present review, we will focus on the roles of nebulin family members in the heart. NebulinMutations in the nebulin gene are causative for nemaline myopathy 24,25 and the function of nebulin in skeletal muscle has been extensively studied both in vitro and in vivo, revealing its multifunctional role in various processes required for efficient myofibrillar force generation, including (1) regulation he nebulin family of actin-binding cytoskeletal proteins comprises nebulin, nebulette, N-RAP (Nebulinrelated anchoring protein), LASP-1 (LIM and Src homology 3 (SH3) Protein-1), and LASP-2 (LIM and SH3 Protein-2/LIM-Nebulette), a splice variant of nebulette. 1 The members of the family contain various numbers of 35-residue nebulin repeats, containing a central conserved SDXXYK consensus motif 2,3 and named after the founding member nebulin, which includes up to 185 copies of the repeat (Figure). 4,5 Nebulin is the largest member of the nebulin family, with a molecular weight ranging from 600 to 900 kDa and expressed predominantly in skeletal muscle, where it stretches along the actin thin filament with its C-terminal region anchored in the sarcomeric Z-line and its N-terminal region extending towards the pointed end of the thin filament. 4,6 For reviews on the sarcomere and the Z-line, see Frank et al 7 and Sheikh et al. 8 Within the central part of nebulin (repeats 9-162), the nebulin repeats are organized into "super repeats" of 7 repeats, containing a conserved WLKGIGW motif at the end of the third repeat of each super repeat. 4 Each nebulin repeat binds to an actin monomer, 9-12 while the nebulin super repeats correspond to the architecture of the thin filament with 1 tropomyosin/ troponin complex for every 7 actin subunits, and interact with troponin T and tropomyosin along the length of the thin fila- Roles of Nebulin Family Members in the HeartMarie-Louise Bang, PhD; Ju Chen, PhDThe members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, ...

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“…The CMYA1-repeat proteins are novel ligands of the SH3 domains of nebulin and nebulette. Furthermore, during muscle damage, the CMYA1-repeat proteins play a role in myofibril assembly (Eulitz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Promoter analysis of bovine cardiomyopathy-associated protein 1 gene

et al. 2016

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ABSTRACT. The CMYA1 (cardiomyopathy-associated protein 1) is an actin-binding protein that plays a vital role in cardiac morphogenesis. CMYA1 is expressed specifically in the myocardial and skeletal muscle and is up-regulated in injured muscle. We therefore speculated that the bovine CMYA1 promoter might be muscle-specific. In this study, the promoter (+20/-1135) region of the bovine CMYA1 gene was cloned into a pEGFP-1 vector, and we found that the EGFP was observed only in C2C12 and myoblast cells. Thus, the CMYA1 promoter is musclespecific. Thereafter, eight pGL3-basic vectors with various truncated CMYA1 promoter fragments were transfected into C2C12 cells, to identify the core promoter region using a Dual-Luciferase Reporter Assay System. The results showed that the promoter region from -457 to +20 bp was essential for CMYA1 to maintain the promoter activity, implying that this region may be the CMYA1 core promoter. We thus illustrate that the core promoter is muscle-specific. To evaluate the activity of the CMYA1 core promoter, the CMYA1 core and muscle creatine kinase (MCK) promoters were cloned into a pcDNA3.1 vector. The expression levels of their target genes were measured in C2C12 cells using real-time polymerase chain reaction. The CMYA1 promoter drove the expression of the target gene six times higher than did the MCK promoter. The results thus suggest that the CMYA1 promoter could be an effective muscle-specific promoter, which may be useful in further studies of cardiomyopathy treatment and transgenic animal research.

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Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling

Cited by 35 publications

References 71 publications

Nebulin, a multi-functional giant

Nebulin, a multi-functional giant

Roles of Nebulin Family Members in the Heart

Promoter analysis of bovine cardiomyopathy-associated protein 1 gene

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