Towards a Molecular Understanding of the Elasticity of Titin

Linke, Wolfgang A.; Ivemeyer, Marc; Olivieri, Nicoletta; Kolmerer, Bernhard; Rüegg, J. C.; Labeit, Siegfried

doi:10.1006/jmbi.1996.0441

Cited by 269 publications

(258 citation statements)

References 48 publications

(75 reference statements)

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“…Here, librational entropy would oppose the over-stretch of the poly-Ig chain, acting as an energy barrier that protects it from domain unfolding by triggering, instead, the unraveling of the more compliant PEVK sequences in neighboring springs. As a result, the interplay of poly-Ig and PEVK serial springs causes a nonlinear response to stretch that defines the mechanical properties of titin (3,5).…”

Section: Conservation Of Intermodular Transitionmentioning

confidence: 99%

“…These methodologies finger-print unfolding phenotypes determined by the secondary structure elements of the Ig fold (i.e., analyze events at the module level) but do not report on the behavior of the chain. Because domain unfolding is unlikely to drive titin elasticity at physiological loads (3,5), elucidating the structure and dynamics of the titin chain (at a level higher than the Ig module) is crucial to establish its mechanistic principles. To date, atomic models of domain tandems from titin have been scarce and limited to the N-terminal Ig-doublet Z1Z2 (6, 7) part of the Z-disk, and A168-A170 (8) (subfragment in 9) located at the M-line near the C terminus of the filament.…”

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confidence: 99%

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A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain

Castelmur

Marino

Svergun

et al. 2008

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

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Myofibril elasticity, critical to muscle function, is dictated by the intrasarcomeric filament titin, which acts as a molecular spring. To date, the molecular events underlying the mechanics of the folded titin chain remain largely unknown. We have elucidated the crystal structure of the 6-Ig fragment I65-I70 from the elastic I-band fraction of titin and validated its conformation in solution using small angle x-ray scattering. The long-range properties of the chain have been visualized by electron microscopy on a 19-Ig fragment and modeled for the full skeletal tandem. Results show that conserved Ig-Ig transition motifs generate high-order in the structure of the filament, where conformationally stiff segments interspersed with pliant hinges form a regular pattern of dynamic super-motifs leading to segmental flexibility in the chain. Pliant hinges support molecular shape rearrangements that dominate chain behavior at moderate stretch, whereas stiffer segments predictably oppose high stretch forces upon full chain extension. There, librational entropy can be expected to act as an energy barrier to prevent Ig unfolding while, instead, triggering the unraveling of flanking springs formed by proline, glutamate, valine, and lysine (PEVK) sequences. We propose a mechanistic model based on freely jointed rigid segments that rationalizes the response to stretch of titin Ig-tandems according to molecular features.electron microscopy ͉ poly-Ig tandem structure ͉ small angle x-ray scattering ͉ titin elasticity ͉ x-ray crystallography T he striated muscle of vertebrate is characterized by a striking elasticity that allows it to store mechanical energy and stretch over twice its resting length without disrupting its structural integrity. At physiological amounts of stretch, most of the elastic response of the myofibril is generated by the intrasarcomeric titin filament (Ϸ3.2 MDa, Ͼ1-m length). This protein functions as a bidirectional spring that stretches and recoils during muscle function to return the myofibril to its resting length (1). The spring components of titin are located in its I-band fraction, which forms an elastic connection between the ends of the thick filaments and the Z-disk. Titin contains two main elastic components, a prolinerich PEVK (proline, glutamate, valine, and lysine) segment of up to 2,200 residues length and a poly-Ig array formed by up to 95 modules (2). Both segments straighten upon myofibril stretch developing a passive entropic tension in the sarcomere. Poly-Ig arrays extend at low force whereas PEVK-repeats unravel at higher load, with the combined action of both springs defining the mechanical stiffness of the sarcomere (1, 3). The importance of stretch-recoil control in muscle function is emphasized by the finely tuned composition of both poly-Ig and PEVK segments in titin, which through splicing undergo an extensive adaptation to the different physiological and pathological states of muscle.The molecular basis of titin chain elasticity is currently unknown. The response to stretch of i...

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Section: Conservation Of Intermodular Transitionmentioning

confidence: 99%

mentioning

confidence: 99%

A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain

Castelmur

Marino

Svergun

et al. 2008

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

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“…Titin is a tandem array of Ig type C2 and fibronectin (FN) type III domains (Ϸ300 per molecule) interspersed with unique sequences, most notably the Pro-, Glu-, Val-, and Lys-rich PEVK segment, and the N2A and N2B segments (5). The I-band segment of titin acts as a molecular spring, whose elastic properties define the passive or restoring mechanical properties of striated muscle (6)(7)(8)(9). By contrast, titin's A-band segment is thought to function as a scaffold that defines structural regularity within the A band (10).…”

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confidence: 99%

Global configuration of single titin molecules observed through chain-associated rhodamine dimers

Grama

Somogyi

Kellermayer

2001

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

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The global configuration of individual, surface-adsorbed molecules of the giant muscle protein titin, labeled with rhodamine conjugates, was followed with confocal microscopy. Fluorescence-emission intensity was reduced because of self-quenching caused by the close spacing between rhodamine dye molecules that formed dimers. In the presence of chemical denaturants, fluorescence intensity increased, reversibly, up to 5-fold in a fast reaction; the kinetics were followed at the single-molecule level. We show that dimers formed in a concentrated rhodamine solution dissociate when exposed to chemical denaturants. Furthermore, titin denaturation, followed by means of tryptophan fluorescence, is dominated by a slow reaction. Therefore, the rapid fluorescence change of the single molecules reflects the direct action of the denaturants on rhodamine dimers rather than the unfolding͞refolding of the protein. Upon acidic denaturation, which we have shown not to dissociate rhodamine dimers, fluorescence intensity change was minimal, suggesting that dimers persist because the unfolded molecule has contracted into a small volume. The highly contractile nature of the acid-unfolded protein molecule derives from a significant increase in chain flexibility. We discuss the potential implications this finding could have for the passive mechanical behavior of striated muscle.T itins are 3.0-3.7 MDa filamentous proteins extending between the Z-and M-lines of the sarcomere (1-4). Titin is a tandem array of Ig type C2 and fibronectin (FN) type III domains (Ϸ300 per molecule) interspersed with unique sequences, most notably the Pro-, Glu-, Val-, and Lys-rich PEVK segment, and the N2A and N2B segments (5). The I-band segment of titin acts as a molecular spring, whose elastic properties define the passive or restoring mechanical properties of striated muscle (6-9). By contrast, titin's A-band segment is thought to function as a scaffold that defines structural regularity within the A band (10). Recent single-molecule experiments often have used titin as a model system because of a large size that makes it relatively easily accessible to such investigations. Single-molecule-mechanics experiments using either optical tweezers (11-13) or atomic force microscopy (AFM; ref. 14) described titin as an entropic chain in which domain unfolding occurs at high forces and refolding occurs at low forces. These experiments formed the basis of many theoretical and modeling works that addressed the mechanisms of mechanically driven protein folding (15)(16)(17)(18)(19)(20). Individual titin molecules can be made visible under aqueous conditions after labeling with fluorophores. Fluorescently labeled titin molecules have recently been studied under various conditions: equilibration to a surface (21-23), stretching with meniscus force (22, 23) and direct manipulation (24), and chemical denaturation (25,26). Chemical denaturation has been shown to cause an abrupt and significant rise in the fluorescence intensity of Oregon Green 488 (Molecular Probes) maleimi...

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“…However, that theory would not explain passive resting muscle tone at neutral lengths or at physiological extensions. Another molecular component, called titin, has been demonstrated to exert passive tension in cardiac muscle and in considerably stretched skeletal muscle (38,39) . However, its elastic role in the multifidus muscle was not supported at neutral or extended lengths (40) .…”

Section: Resting (Static) Myofascial Tone Mainly Helps To Stabilize Bmentioning

confidence: 99%

Clinical, Biomechanical, and Physiological Translational Interpretations of Human Resting Myofascial Tone or Tension

Masi

Nair²,

Evans³

et al. 2010

IJTMB

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Methods: Biomechanical, clinical, and physiological studies were reviewed to interpret the passive stiffness properties of HRMT that help to stabilize various relaxed functions such as quiet balanced standing. Biomechanical analyses and experimental studies of the lumbar multifidus were reviewed to interpret its passive stiffness properties. The lumbar multifidus was illustrated as the major core stabilizing muscle of the spine, serving an important passive biomechanical role in the body.Results: Research into muscle physiology suggests that passive resting tension (CNS-independent) is generated in sarcomeres by the molecular elasticity of low-level cycling cross-bridges between the actomyosin filaments. In turn, tension is complexly transmitted to intimately enveloping fascial matrix fibrils and other molecular elements in connective tissue, which, collectively, constitute the myofascial unit. Postural myofascial tonus varies with age and sex. Also, individuals in the population are proposed to vary in a polymorphism of postural HRMT. A few people are expected to have outlier degrees of innate postural hypotonicity or hypertonicity. Such biomechanical variations likely predispose to greater risk of related musculoskeletal disorders, a situation that deserves greater attention in clinical practice and research. Axial myofascial hypertonicity was hypothesized to predispose to ankylosing spondylitis. This often-progressive deforming condition of vertebrae and sacroiliac joints is characterized by stiffness features and particular localization of bony lesions at entheseal sites. Such unique features imply concentrations and transmissions of excessive force, leading to tissue micro-injury and maladaptive repair reactions.Conclusions: The HRMT model is now expanded and translated for clinical relevance to therapists. Its passive role in helping to maintain balanced postures is supported by biomechanical principles of myofascial elasticity, tension, stress, stiffness, and tensegrity. Further research is needed to determine the molecular basis of HRMT in sarcomeres, the transmission of tension by the enveloping fascial elements, and the means by which the myofascia helps to maintain efficient passive postural balance in the body. Significant deficiencies or excesses of postural HRMT may predispose to symptomatic or pathologic musculoskeletal disorders whose mechanisms are currently unexplained.

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Towards a Molecular Understanding of the Elasticity of Titin

Cited by 269 publications

References 48 publications

A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain

A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain

Global configuration of single titin molecules observed through chain-associated rhodamine dimers

Clinical, Biomechanical, and Physiological Translational Interpretations of Human Resting Myofascial Tone or Tension

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