The titin cDNA sequence and partial genomic sequences: Insights into the molecular genetics, cell biology and physiology of the titin filament system

Kolmerer, Bernhard; Witt, Christian; Freiburg, Alexandra; Millevoi, Stefania; Stier, Günter; Sorimachi, Hiroyuki; Pelin, Katarina; Carrier, Lucie; Schwartz, Ketty; Labeit, D.; Gregorio, Carol C.; Linke, Wolfgang A.; Labeit, Siegfried

doi:10.1007/bf02346659

Cited by 9 publications

(14 citation statements)

References 74 publications

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“…Titin family members such as vertebrate titin, Drosophila Projectin, and C. elegans Twitchin are characterized by the presence of not only Ig domains, but also a kinase domain and fibronectin type III repeats (Labeit and Kolmerer, 1995; Benian et al, 1999). The PEVK domain, rich in proline, glutamic acid, valine, and lysine, and possibly involved in elasticity, is specific to titin (Kolmerer et al, 1999). Thus, we searched for these sequences in Kettin, but no homology was found.…”

Section: Resultsmentioning

confidence: 99%

“…In IFM, Projectin is detected in the I-band, whereas, in other muscles, it is situated solely in the A-band, suggesting that Pro-jectin may have different functions depending on muscle types (Vigoreaux et al, 1991). As with titin, Projectin and Twitchin possess fibronectin type III and protein kinase domains (for reviews see Benian et al, 1999; Kolmerer et al, 1999). Super-repeats consisting of fibronectin type III and Ig domains may be important for the putative ruler function of titin, whereas the kinase domain may be involved in regulatory processes (for reviews see Gautel et al, 1999; Kolmerer et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Requirements of Kettin, a Giant Muscle Protein Highly Conserved in Overall Structure in Evolution, for Normal Muscle Function, Viability, and Flight Activity of Drosophila

Hakeda

Endo

Saigo

2000

The Journal of Cell Biology

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Kettin is a giant muscle protein originally identified in insect flight muscle Z-discs. Here, we determined the entire nucleotide sequence of Drosophila melanogaster kettin, deduced the amino acid sequence of its protein product (540 kD) along with that of the Caenorhabditis elegans counterpart, and found that the overall primary structure of Kettin has been highly conserved in evolution. The main body of Drosophila Kettin consists of 35 immunoglobulin C2 domains separated by spacers. The central two thirds of spacers are constant in length and share in common two conserved motifs, putative actin binding sites. Neither fibronectin type III nor kinase domains were found. Kettin is present at the Z-disc in several muscle types. Genetic analysis showed that kettin is essential for the formation and maintenance of normal sarcomere structure of muscles and muscle tendons. Accordingly, embryos lacking kettin activity cannot hatch nor can adult flies heterozygous for the kettin mutation fly.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Requirements of Kettin, a Giant Muscle Protein Highly Conserved in Overall Structure in Evolution, for Normal Muscle Function, Viability, and Flight Activity of Drosophila

Hakeda

Endo

Saigo

2000

The Journal of Cell Biology

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“…This portion of titin consists of a serine/threonine kinase domain that is encoded within M-band exon 1 (Mex-1) and 10 Ig-CII globular motifs (MIg1-MIg10), each composed of seven antiparallel β -sheets, interspersed by unique interdomain sequences (Is1-Is7) of varying lengths and properties that are encoded within M-line exons 2–6 (Mex2-Mex6) (49, 98, 123, 130, 191). Five of the six exons that encode the M-band portion of titin are constitutively expressed in all types of muscles throughout embryonic development and in adulthood, but exon 5 (Mex5), which contains a binding site for calpain-3, is alternatively spliced and its expression varies widely among muscles (173, 174). For instance, 90% of titin molecules in heart, soleus, and psoas (slow-twitch muscles), but only 10% in extensor digitorum longus and tibialis anterior (fast-twitch muscles) contain Mex5.…”

Section: Titinmentioning

confidence: 99%

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Kontrogianni‐Konstantopoulos

Ackermann

Bowman³

et al. 2009

Physiological Reviews

217

259

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Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3–4 MDa), nebulin (600–800 kDa), and obscurin (~720–900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. There is a large amount of data showing that each of these molecules interacts with several to many different protein ligands, regulating their activity and localizing them to particular sites within or surrounding sarcomeres. Consistent with this, mutations in each of these proteins have been linked to skeletal and cardiac myopathies or to muscular dystrophies. The evidence that any of them plays a role as a “molecular template,” “molecular blueprint,” or “molecular ruler” is less definitive, however. Here we review the structure and function of titin, nebulin, and obscurin, with the literature supporting a role for them as scaffolding molecules and the contradictory evidence regarding their roles as molecular guides in sarcomerogenesis.

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“…It has also been shown that a negatively charged region of titin near the elastic PEVK region at the A abnd/I band interface may be involved in Ca 2+ binding in µM quantities [Tatsumi et al, 2001. Additionally, it has been suggested that physiological functions of titin are mediated by this Ca 2+ binding [Kolmerer et al, 1999.…”

Section: Discussionmentioning

confidence: 99%

Identification of skeletal muscle autoantigens by expression library screening using sera from autoimmune rippling muscle disease (ARMD) patients

Watkins

Zelinka

Kesic

et al. 2006

J of Cellular Biochemistry

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Novel forms of contractile regulation observed in skeletal muscle are evident in neuromuscular diseases like rippling muscle disease (RMD). Previous studies of an autoimmune form of RMD (ARMD) identified a very high molecular weight skeletal muscle protein antigen recognized by ARMD patient antisera. This study utilized ARMD and myasthenia gravis (MG) patient antisera, to screen a human skeletal muscle cDNA library that subsequently identified proteins that could play a role in ARMD. Based on nucleotide sequence analysis, three distinct ARMD antigens were identified: titin Isoform N2A, ATP synthase 6, and PPP1R3 (protein phosphatase 1 regulatory subunit 3). The region of titin identified by ARMD antisera is distinct from the main immunogenic region (MIR) recognized by classical MG antibodies. Sera from classical MG patient identifies an expressed sequence corresponding to the titin MIR. Although the mechanism of antibody penetration is not known, previous studies have shown that rippling muscle antibodies affect the contractile machinery of myofibers resulting in mechanical sensitivity. Titin's role as a modulator of muscle contractility makes it a potential target in understanding muscle mechanosensitive regulation.

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The titin cDNA sequence and partial genomic sequences: Insights into the molecular genetics, cell biology and physiology of the titin filament system

Cited by 9 publications

References 74 publications

Requirements of Kettin, a Giant Muscle Protein Highly Conserved in Overall Structure in Evolution, for Normal Muscle Function, Viability, and Flight Activity of Drosophila

Requirements of Kettin, a Giant Muscle Protein Highly Conserved in Overall Structure in Evolution, for Normal Muscle Function, Viability, and Flight Activity of Drosophila

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Identification of skeletal muscle autoantigens by expression library screening using sera from autoimmune rippling muscle disease (ARMD) patients

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