Evidence for the Oligomeric State of ‘Elastic’ Titin in Muscle Sarcomeres

Houmeida, Ahmed; Baron, Andy; Keen, Jeff N.; Khan, Ghulam N.; Knight, Peter J.; Stafford, Walter F.; Thirumurugan, Kavitha; Thompson, Beatrix; Tskhovrebova, Larissa; Trinick, John

doi:10.1016/j.jmb.2008.09.030

Cited by 19 publications

(23 citation statements)

References 48 publications

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“…A comparison of the I103 epitope with the thick filament length in WT and Ttn ΔIAjxn mice shows that the deleted region spans in WT from ∼30 nm inside to ∼30 nm outside the edge of the A band. Considering that in the thick filament region six titin molecules are likely organized as three separate dimers on the outside of the thick filament (23), but in the distal tandem Ig segment titin appears to be organized in side-to-side hexamers (24), the IA junction might play a role in organizing the transition between these two distinct types of organization.…”

Section: La Of Hom Ttnmentioning

confidence: 99%

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Granzier

Hutchinson

Tonino

et al. 2014

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

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Titin, the largest protein known, forms a giant filament in muscle where it spans the half sarcomere from Z disk to M band. Here we genetically targeted a stretch of 14 immunoglobulin-like and fibronectin type 3 domains that comprises the I-band/A-band (IA) junction and obtained a viable mouse model. Super-resolution optical microscopy (structured illumination microscopy, SIM) and electron microscopy were used to study the thick filament length and titin's molecular elasticity. SIM showed that the IA junction functionally belongs to the relatively stiff A-band region of titin. The stiffness of A-band titin was found to be high, relative to that of I-band titin (∼40-fold higher) but low, relative to that of the myosin-based thick filament (∼70-fold lower). Sarcomere stretch therefore results in movement of A-band titin with respect to the thick filament backbone, and this might constitute a novel lengthsensing mechanism. Findings disproved that titin at the IA junction is crucial for thick filament length control, settling a long-standing hypothesis. SIM also showed that deleting the IA junction moves the attachment point of titin's spring region away from the Z disk, increasing the strain on titin's molecular spring elements. Functional studies from the cellular to ex vivo and in vivo left ventricular chamber levels showed that this causes diastolic dysfunction and other symptoms of heart failure with preserved ejection fraction (HFpEF). Thus, our work supports titin's important roles in diastolic function and disease of the heart. passive stiffness | molecular elasticity | hypertrophy | mechanosensing

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Section: La Of Hom Ttnmentioning

confidence: 99%

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Granzier

Hutchinson

Tonino

et al. 2014

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

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“…Based on three-dimensional single-particle analysis of electron-microscopy micrographs, Aband titin might exist in pairs (Al Khayat et al, 2013;Zoghbi et al, 2008). The distal tandem Ig segment has been suggested to form a higher-order structure of a side-to-side hexamer (Houmeida, et al, 2008). Nevertheless, the orientation and localization of titin along the sarcomere is not sufficiently resolved.…”

Section: Modulation Of Force Development Kinetics By Titinmentioning

confidence: 99%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca 2+ -induced force development (rate constant k ACT ), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 mm) and rapidly activated with Ca 2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant k TR ) were determined by slackening and re-stretching myofibrils during Ca 2+ -mediated activation. Myofibrils from knockout mice exhibited significantly higher k ACT , k TR and maximum Ca 2+ -activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca 2+ ] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating crossbridges without decelerating relaxation.

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“…Whether titin runs through the I-band as a single molecular strand or as a selfassociated oligomer is largely unknown. However, evidence was provided for an ϳ100-nm-long stalk-like structure emanating from the thick filament (the "end filament"), which presumably represents a bundle of six self-associated titin molecules (3). In the A-band, titin may be organized as a dimer in a helical conformation (4).…”

Section: Titin: Backbone Of the Sarcomerementioning

confidence: 99%

“…A-band titin, the largest part of the molecule, again is constitutively expressed in heart and skeletal muscles. As soon as titin joins the thick filament, a second ␤-sheet domain type next to the Ig domain appears, the fibronectin type 3 (FN3) 3 domain, which makes up the majority of A-band titin (Fig. 1).…”

Section: Constitutively and Differentially Expressed Titin Regionsmentioning

confidence: 99%

The Giant Protein Titin: A Regulatory Node That Integrates Myocyte Signaling Pathways

Krüger

Linke

2011

Journal of Biological Chemistry

148

125

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Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control.The specialized cytoskeleton of striated muscle cells consists of highly ordered structures, the sarcomeres, which are built of myosin, actin, and titin filaments (Fig. 1), along with a plethora of other structural and regulatory proteins. The cytoskeleton is no longer seen as a static skeleton that fixes each cellular component but as a dynamic and sensitive cellular organizer that responds to various extracellular clues. Muscle cells are no exception to this; however, some responses to external signals are unique to myocytes due to the specialized protein composition and ordered arrangement of the sarcomeres. In this minireview, we first provide general information on the structure and function of the giant muscle protein titin (also known as connectin) and then focus on the dynamic role of titin as an important regulatory node in the sarcomeric cytoskeleton. Special attention is paid to emerging evidence suggesting that phosphorylation by various protein kinases alters titin function.

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Evidence for the Oligomeric State of ‘Elastic’ Titin in Muscle Sarcomeres

Cited by 19 publications

References 48 publications

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

The Giant Protein Titin: A Regulatory Node That Integrates Myocyte Signaling Pathways

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