Nebulin: A Study of Protein Repeat Evolution

Björklund, Åsa K.; Light, Sara; Sagit, Rauan; Elofsson, Arne

doi:10.1016/j.jmb.2010.07.011

Cited by 46 publications

(46 citation statements)

References 42 publications

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“…Nebulin is the largest member of an evolutionary conserved tandem-repeat protein family in vertebrates (Bjorklund et al, 2010). Members of this family include nebulin, N-RAP, LASP-1, LASP-2 and nebulette (Kontrogianni-Konstantopoulos et al, 2009;Labeit et al, 2011;Pappas et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The desmin coil 1B mutation K190A impairs nebulin Z-disc assembly and destabilizes actin thin filaments

Conover

Gregorio

2011

Journal of Cell Science

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SummaryDesmin intermediate filaments intimately surround myofibrils in vertebrate muscle forming a mesh-like filament network. Desmin attaches to sarcomeres through its high-affinity association with nebulin, a giant F-actin binding protein that co-extends along the length of actin thin filaments. Here, we further investigated the functional significance of the association of desmin and nebulin in cultured primary myocytes to address the hypothesis that this association is key in integrating myofibrils to the intermediate filament network. Surprisingly, we identified eight peptides along the length of desmin that are capable of binding to C-terminal modules 160-170 in nebulin. In this study, we identified a targeted mutation (K190A) in the desmin coil 1B region that results in its reduced binding with the nebulin C-terminal modules. Using immunofluorescence microscopy and quantitative analysis, we demonstrate that expression of the mutant desmin K190A in primary myocytes results in a significant reduction in assembled endogenous nebulin and desmin at the Z-disc. Non-uniform actin filaments were markedly prevalent in myocytes expressing GFP-tagged desmin K190A, suggesting that the nearcrystalline organization of actin filaments in striated muscle depends on a stable interaction between desmin and nebulin. All together, these data are consistent with a model in which Z-disc-associated nebulin interacts with desmin through multiple sites to provide efficient stability to satisfy the dynamic contractile activity of myocytes.

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Section: Discussionmentioning

confidence: 99%

The desmin coil 1B mutation K190A impairs nebulin Z-disc assembly and destabilizes actin thin filaments

Conover

Gregorio

2011

Journal of Cell Science

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“…It has been suggested that the TRI region is the result of two tandem duplications through Alu-mediated homologous recombination in an ancestor of human and chimpanzee. 14 One of the most common mechanisms inducing CNVs is thought to be non-allelic homologous recombination (NAHR) caused by misalignment and cross-over of non-allelic homologous DNA segments, such as low copy repeats. CNV breakpoints have also been shown to frequently reside in regions of repeat elements.…”

Section: Introductionmentioning

confidence: 99%

A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array

et al. 2015

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Recently, new large variants have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and disease-causing variants in NEB are a main cause of the recessively inherited form of NM. NEB consists of 183 exons and it includes homologous sequences such as a 32-kb triplicate region (TRI), where eight exons are repeated three times (exons 82-89, 90-97, 98-105). In human, the normal copy number of NEB TRI is six (three copies in each allele). Recently, we described a custom NM-CGH microarray designed to detect copy number variations (CNVs) in the known NM genes. The array has now been updated to include all the currently known 10 NM genes. The NM-CGH array is superior in detecting CNVs, especially of the NEB TRI, that is not included in the exome capture kits. To date, we have studied 266 samples from 196 NM families using the NM-CGH microarray, and identified a novel recurrent NEB TRI variation in 13% (26/196) of the families and in 10% of the controls (6/60). An analysis of the breakpoints revealed adjacent repeat elements, which are known to predispose for rearrangements such as CNVs. The control CNV samples deviate only one copy from the normal six copies, whereas the NM samples include CNVs of up to four additional copies. Based on this study, NEB seems to tolerate deviations of one TRI copy, whereas addition of two or more copies might be pathogenic.

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“…However, in the case of repeated proteins it is clear that the duplication of particular domain combinations are strongly favored [8]. The large length variation caused by indels of several protein repeat domains affects binding properties of the proteins, i.e.…”

Section: Introductionmentioning

confidence: 99%

Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins

Light

Sagit

Ekman

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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This is an accepted version of a paper published in Biochimica et Biophysica ActaProteins and Proteomics. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the published paper: Light, S., Sagit, R., Ekman, D., Elofsson, A. (2013) "Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins" Biochimica et Biophysica Acta -Proteins and Proteomics, 1834(5): 890-897 Access to the published version may require subscription. AbstractProteins evolve through point mutations as well as by insertions and deletions (indels). During the last decade it has become apparent that protein regions that do not fold into three-dimensional structures, i.e. intrinsically disordered regions, are quite common. Here, we have studied the relationship between protein disorder and indels using HMM-HMM pairwise alignments in two sets of orthologous eukaryotic protein pairs. First, we show that disordered residues are much more frequent among indel residues than among aligned residues and, also are more prevalent among indels than in coils. Second, we observed that disordered residues are particularly common in longer indels. Disordered indels of short-to-medium size are prevalent in the nonterminal regions of proteins while the longest indels, ordered and disordered alike, occur toward the termini of the proteins where new structural units are comparatively well tolerated. Finally, while disordered regions often evolve faster than ordered regions and disorder is common in indels, there are some previously recognized protein families where the disordered region is more conserved than the ordered region. We find that these rare proteins are often involved in information processes, such as RNA processing and translation.

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Nebulin: A Study of Protein Repeat Evolution

Cited by 46 publications

References 42 publications

The desmin coil 1B mutation K190A impairs nebulin Z-disc assembly and destabilizes actin thin filaments

The desmin coil 1B mutation K190A impairs nebulin Z-disc assembly and destabilizes actin thin filaments

A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array

Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins

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