Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

Arimura, Takuro; Nakamura, Tomohisa; Hiroi, Shitoshi; Satoh, Manatsu; Takahashi, Megumi; Ohbuchi, Nobuhisa; Ueda, Kazuo; Nouchi, Toshihiko; Yamaguchi, Noriko; Akai, Jun; Matsumori, Akira; S, Sasayama; Kimura, Akinori

doi:10.1007/s004390000389

Cited by 51 publications

(35 citation statements)

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“…This gene spanned 390 kb and encompassed seven exons. Surprisingly, the last three exons of the novel gene were found to be identical to three exons from the 3Ј part of the human gene for the cytoskeletal protein nebulette (27). We therefore concluded that the novel protein must represent a splice variant of human nebulette.…”

Section: Identification Of Human and Mouse Lim-nebulette-exten-mentioning

confidence: 80%

“…Furthermore, defects in the nebulette gene are associated with the nonfamilial form of idiopathic dilated cardiomyopathy, which is characterized by a thinwalled heart (27). We have argued that LIM-nebulette might play a role in the assembly of focal adhesions similar to the role played by nebulin and nebulette in the assembly of the sarcomeric Z-disks.…”

Section: Fig 4 Interaction Of Zyxin With Lasp-1 As Demonstrated By mentioning

confidence: 98%

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Zyxin Interacts with the SH3 Domains of the Cytoskeletal Proteins LIM-nebulette and Lasp-1

Zhuang

Trüeb

2004

Journal of Biological Chemistry

142

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Focal adhesions are essential cellular structures of metazoan organisms that link the extracellular matrix to the cytoskeleton. The controlled assembly and disassembly of focal adhesions is critical for a diversity of biological functions, including cell adhesion, motility, and spreading. Typically, focal adhesions are found at sites where a number of proteins from different signaling pathways converge to respond to extracellular signals (1). Thus far, more than 50 different focal adhesion proteins have been identified (2). Among them are several adapter proteins with protein-protein interaction motifs that play an important role in the dynamic assembly of focal adhesions.One of these adapter proteins is zyxin. Zyxin was originally identified in chicken fibroblasts as a protein associated with stress fibers and focal adhesions (3). The mammalian homologue of avian zyxin was subsequently cloned from a subtracted cDNA library enriched with clones that are down-regulated in transformed fibroblasts (4). At the same time, human zyxin was also cloned from umbilical vein endothelial cells by crosshybridization (5). Analysis of the protein sequence revealed the typical structure of a multidomain protein. At the C terminus, zyxin contains three LIM domains arranged in tandem. LIM domains are cysteine-rich motifs with two zinc finger-like structures that mediate specific protein-protein interactions. Three different binding partners for the LIM domains of zyxin have been identified, namely, the cysteine-rich protein CRP, the adapter protein p130cas, and the tumor suppressor protein H-warts/LATS1 (6 -8). At the N terminus, zyxin features an extended, proline-rich domain, which contains a nuclear export signal and several proline clusters. By virtue of these proline clusters, zyxin binds to proteins of the Ena/VASP family, which control the assembly and disassembly of actin filaments (9). The proline clusters also serve as docking sites for the oncoprotein Vav, a nucleotide exchange factor for the Rho family of GTPases (10). Moreover, the extended N-terminal domain is responsible for the interaction of zyxin with the actin-bundling protein ␣-actinin (11). We have recently demonstrated that a linear sequence motif found at the extreme N terminus of zyxin is essential for this interaction (12, 13). Our observation is supported by the fact that LPP (lipoma preferred partner), another member of the zyxin family containing the same linear motif, binds to ␣-actinin, too (14).Several pieces of evidence from different lines of investigation suggest that zyxin might play an important role in the organization of the actin cytoskeleton. Zyxin induces the polymerization of actin on the surface of mitochondria when artificially targeted to these ectopic sites (15,16). Actin polymerization and the resulting tension appear to be crucial for the dynamic assembly of focal adhesions (1). On the other hand, zyxin is one of the first molecules that dissociate from dissolving focal adhesions (17). This observation raises the intriguing possibil...

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Section: Identification Of Human and Mouse Lim-nebulette-exten-mentioning

confidence: 80%

Section: Fig 4 Interaction Of Zyxin With Lasp-1 As Demonstrated By mentioning

confidence: 98%

Zyxin Interacts with the SH3 Domains of the Cytoskeletal Proteins LIM-nebulette and Lasp-1

Zhuang

Trüeb

2004

Journal of Biological Chemistry

142

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“…As a number of missense mutations in genes encoding for titin and titin-associated proteins have recently been reported to be responsible for DCM, 3,[12][13][14][15][19][20][21][22][23][24][25] we searched in a well-characterized sample of DCM patients for unknown SNPs and/or mutations in the human MYPN and ANKRD1 genes. In order to extend our knowledge on disease-causing mutations in these two proteins expressed in heart tissue, we screened the coding sequences and corresponding intron flanks of the two genes and found two novel non-synonymous mutations in the MYPN gene and only one rare synonymous SNP in the coding region of the ANKRD1 gene.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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on behalf of the German Competence Network Heart Failure Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARPencoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the a-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and a-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T4C and c.-79C4T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

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“…63 More recently, 4 heterozygous missense mutations (K60N, Q128R, G202R, A592E) with different locations within the nebl gene were identified in patients with DCM and absent from 300 ethnically matched control subjects. 64 The 4 variants are all localized in the nebulin repeat region with the K60N, Q128R, G202R, and A592E variants residing in nebulin repeats 1, 3, 5, and 16, respectively (Figure).…”

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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Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

Cited by 51 publications

References 54 publications

Zyxin Interacts with the SH3 Domains of the Cytoskeletal Proteins LIM-nebulette and Lasp-1

Zyxin Interacts with the SH3 Domains of the Cytoskeletal Proteins LIM-nebulette and Lasp-1

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

Roles of Nebulin Family Members in the Heart

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