Binding of a native titin fragment to actin is regulated by PIP2

Astier, Catherine; Raynaud, Fabrice; Lebart, Marie‐Christine; Roustan, Claude; Benyamin, Yves

doi:10.1016/s0014-5793(98)00572-9

Cited by 35 publications

(22 citation statements)

References 39 publications

(42 reference statements)

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“…Consistent with this, Astier et al (13) calculated an apparent binding affinity ( K D ) in the low micromolar range for the binding of actin to titin's PEVK region, and Kulke et al (188) and Yamasaki et al (418) proposed that this binding might be modulated by dynamic extrinsic factors, such as local ionic strength and temperature. Using in vitro motility assays and cosedimentation studies, they demonstrated that increases in ionic strength or temperature augmented binding significantly, which suggested the involvement of hydrophobic interactions in the association of actin with the PEVK region of titin (188, 418).…”

Section: Titinmentioning

confidence: 85%

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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Section: Titinmentioning

confidence: 85%

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Kontrogianni‐Konstantopoulos

Ackermann

Bowman³

et al. 2009

Physiological Reviews

217

259

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“…Recently, a correlation between titin size and TFL was reported based on comparisons of multiple rabbit skeletal muscles [5], and it was suggested therefore that titin may play a role in TFL regulation. Titin could affect TFL directly (titin is known to interact with actin [46–49]) or indirectly, for example by altering the slack sarcomere length. We tested the proposal that titin affects TFL in the heart by using the Rbm20 ΔRRM mouse model in which altered splicing results in titin molecules that are much larger than in wild type mice [35].…”

Section: Discussionmentioning

confidence: 99%

Thin filament length in the cardiac sarcomere varies with sarcomere length but is independent of titin and nebulin

Kolb

Methawasin

et al. 2016

Journal of Molecular and Cellular Cardiology

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Thin filament length (TFL) is an important determinant of the force-sarcomere length (SL) relation of cardiac muscle. However, the various mechanisms that control TFL are not well understood. Here we tested the previously proposed hypothesis that the actin-binding protein nebulin contributes to TFL regulation in the heart by using a cardiac-specific nebulin cKO mouse model (αMHC Cre Neb cKO). Atrial myocytes were studied because nebulin expression has been reported to be most prominent in this cell type. TFL was measured in right and left atrial myocytes using deconvolution optical microscopy and staining for filamentous actin with phalloidin and for the thin filament pointed-end with an antibody to the capping protein Tropomodulin-1 (Tmod1). Results showed that TFLs in Neb cKO and littermate control mice were not different. Thus, deletion of nebulin in the heart does not alter TFL. However, TFL was found to be ~0.05 μm longer in the right than in the left atrium and Tmod1 expression was increased in the right atrium. We also tested the hypothesis that the length of titin’s spring region is a factor controlling TFL by studying the Rbm20ΔRRM mouse which expresses titins that are ~500 kDa (heterozygous mice) and ~1000 kDa (homozygous mice) longer than in control mice. Results revealed that TFL was not different in Rbm20ΔRRM mice. An unexpected finding in all genotypes studied was that TFL increased as sarcomeres were stretched (~0.1 μm per 0.35 μm of SL increase). This apparent increase in TFL reached a maximum at a SL of ~3.0 μm where TFL was ~1.05 μm. The SL dependence of TFL was independent of chemical fixation or the presence of cardiac myosin-binding protein C (cMyBP-C). In summary, we found that in cardiac myocytes TFL varies with SL in a manner that is independent of the size of titin or the presence of nebulin.

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“…The I-band region of titin probably is understood best and consists of the proximal immunoglobulin (Ig) tandem domain segment closest to the Z-disc, the N2A domain, the PEVK segment (rich in proline [P], glutamate [E], valine [V], and lysine [K]), and the distal Ig segment (closest to the A-band) (Fig. Titin also is known to interact with actin in a variety of ways (3,11,29,35,41,44,47), and if the extent of such interactions would change with muscle activation or force production, as has been suggested (54), it would change titin's free spring length and thus its stiffness. The so-called N2B segment is another spring element that is exclusive to cardiac titin.…”

Section: Titin's Stiffness Regulation Titin Structure and Functionmentioning

confidence: 99%