Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Kontrogianni‐Konstantopoulos, Aikaterini; Ackermann, Maegen A.; Bowman, Amber L.; Yap, Solomon; Bloch, Robert J.

doi:10.1152/physrev.00017.2009

Cited by 222 publications

(266 citation statements)

References 427 publications

(822 reference statements)

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“…The human obscurin gene (OBSCN) on chromosome 1q42.13 spans 170 kb and is subject to alternative splicing of its 119 exons, which encode for giant (∼800 kDa) proteins and smaller (∼40-500 kDa) isoforms ( Fig. 1) (Ackermann et al 2014;Fukuzawa et al 2005;Kontrogianni-Konstantopoulos et al 2009;Perry et al 2013;Young et al 2001). The first two-thirds of prototypical human obscurin-A (∼720 kDa) is composed of many immunoglobulin (Ig) and three fibronectin type-III (FnIII) domains, and a single calmodulin-binding IQ motif.…”

Section: Complexity Of the Domain Architectures Of Obscurinsmentioning

confidence: 99%

Obscure functions: the location–function relationship of obscurins

2017

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The obscurin family of polypeptides is essential for normal striated muscle function and contributes to the pathogenesis of fatal diseases, including cardiomyopathies and cancers. The single mammalian obscurin gene, OBSCN, gives rise to giant (∼800 kDa) and smaller (∼40-500 kDa) proteins that are composed of tandem adhesion and signaling motifs. Mammalian obscurin proteins are expressed in a variety of cell types, including striated muscles, and localize to distinct subcellular compartments where they contribute to diverse cellular processes. Obscurin homologs in Caenorhabditis elegans and Drosophila possess a similar domain architecture and are also expressed in striated muscles. The long sought after question, "what does obscurin do?" is complex and cannot be addressed without taking into consideration the subcellular distribution of these proteins and local isoform concentration. Herein, we present an overview of the functions of obscurins and begin to define the intricate relationship between their subcellular distributions and functions in striated muscles.

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Section: Complexity Of the Domain Architectures Of Obscurinsmentioning

confidence: 99%

Obscure functions: the location–function relationship of obscurins

2017

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“…The nebulin domain consists of an α helix in its actinbound form, and the nebulin molecule is believed to extend along the myofibril since the length of one nebulin unit in helical conformation corresponds to the size of one actin monomer. 19 However, the conformation of nebulin in its unbound form is not known. Nebulin units are transient helices in solution, 10 while long constructs of nebulin repeats aggregate at natural pH.…”

Section: Domains and Exons In Nebulin Genesmentioning

confidence: 99%

Nebulin: A Study of Protein Repeat Evolution

Björklund

Light

Sagit

et al. 2010

Journal of Molecular Biology

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Protein domain repeats are common in proteins that are central to the organization of a cell, in particular in eukaryotes. They are known to evolve through internal tandem duplications. However, the understanding of the underlying mechanisms is incomplete. To shed light on repeat expansion mechanisms, we have studied the evolution of the muscle protein Nebulin, a protein that contains a large number of actin-binding nebulin domains.Nebulin proteins have evolved from an invertebrate precursor containing two nebulin domains. Repeat regions have expanded through duplications of single domains, as well as duplications of a super repeat (SR) consisting of seven nebulins. We show that the SR has evolved independently into large regions in at least three instances: twice in the invertebrate Branchiostoma floridae and once in vertebrates.In-depth analysis reveals several recent tandem duplications in the Nebulin gene. The events involve both single-domain and multidomain SR units or several SR units. There are single events, but frequently the same unit is duplicated multiple times. For instance, an ancestor of human and chimpanzee underwent two tandem duplications. The duplication junction coincides with an Alu transposon, thus suggesting duplication through Alu-mediated homologous recombination.Duplications in the SR region consistently involve multiples of seven domains. However, the exact unit that is duplicated varies both between species and within species. Thus, multiple tandem duplications of the same motif did not create the large Nebulin protein.Finally, analysis of segmental duplications in the human genome reveals that duplications are more common in genes containing domain repeats than in those coding for nonrepeated proteins. In fact, segmental duplications are found three to six times more often in long repeated genes than expected by chance.

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“…In this context, the giant proteins of the titin-like family (0.7-4 MDa) are emerging as key mechanotransducers in muscle. Proteins from this family include titin and obscurin in mammals; twitchin, the obscurin homolog UNC-89 and the small TTN-1 titin in nematodes and mollusks; projectin and stretchin in insects (1,2). These proteins are composed of numerous Ig-like domains linked in series and form long filaments embedded in the sarcoskeleton.…”

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Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase

Castelmur

Strümpfer

Franke

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Titin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn 31 -Nlinker-kinase-CRD-Ig 26 ) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N-and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes. molecular mechanobiology | phospho-transfer catalysis | steered molecular dynamics simulations M echanical signals generated during physical activity are critical to the development and regulation of muscle tissue, which undergoes constant adaptation to mechanical demand. Despite the physiological importance of this mechano-feedback, little is known about how mechanical signals are sensed by the myofibril and further translated into biochemical events that feed into the homeodynamics of the tissue. In this context, the giant proteins of the titin-like family (0.7-4 MDa) are emerging as key mechanotransducers in muscle. Proteins from this family include titin and obscurin in mammals; twitchin, the obscurin homolog UNC-89 and the small TTN-1 titin in nematodes and mollusks; projectin and stretchin in insects (1, 2). These proteins are composed of numerous Ig-like domains linked in series and form long filaments embedded in the sarcoskeleton. There, these proteins mediate passive mechanical processes that dictate myofibrillar elasticity and relaxation rates.Titin-like proteins contain a conserved kinase region near their C terminus that consists of Ig-Ig-Fn-linker-kinase-tail-Ig domains. This conservation suggests that titin-like kinases are important members of signaling networks in the sarcomere, although little is known about their cellular context. Titin kinase...

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Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Cited by 222 publications

References 427 publications

Obscure functions: the location–function relationship of obscurins

Obscure functions: the location–function relationship of obscurins

Nebulin: A Study of Protein Repeat Evolution

Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase

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