X-Ray Evidence for a Conformational Change in the Actin-containing Filaments of Vertebrate Striated Muscle

Haselgrove, John C.

doi:10.1101/sqb.1973.037.01.044

Cited by 384 publications

(170 citation statements)

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“…In vertebrate muscle, the intensity of the tropomyosin reflection (I TM ) starts low in relaxed muscle and increases in intensity as tropomyosin moves azimuthally to expose myosin-actin binding sites (6,(23)(24)(25)(26). Here in IFM, we find that I TM is clearly rising and falling during stretch activation (Fig.…”

Section: At Physiological Temperatures (35-40°) Chemically Skinnedmentioning

confidence: 61%

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle

Edwards

Irving

Baumann

et al. 2010

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

108

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Stretch activation is important in the mechanical properties of vertebrate cardiac muscle and essential to the flight muscles of most insects. Despite decades of investigation, the underlying molecular mechanism of stretch activation is unknown. We investigated the role of recently observed connections between myosin and troponin, called "troponin bridges," by analyzing real-time X-ray diffraction "movies" from sinusoidally stretch-activated Lethocerus muscles. Observed changes in X-ray reflections arising from myosin heads, actin filaments, troponin, and tropomyosin were consistent with the hypothesis that troponin bridges are the key agent of mechanical signal transduction. The time-resolved sequence of molecular changes suggests a mechanism for stretch activation, in which troponin bridges mechanically tug tropomyosin aside to relieve tropomyosin's steric blocking of myosin-actin binding. This enables subsequent force production, with crossbridge targeting further enhanced by stretch-induced lattice compression and thick-filament twisting. Similar linkages may operate in other muscle systems, such as mammalian cardiac muscle, where stretch activation is thought to aid in cardiac ejection.S tretch activation is a striking example of mechanical signal transduction, in which stretching a partially activated muscle yields, after a delay, greater activation. It is observed to varying degrees in all striated muscles, is prominent in vertebrate cardiac muscle where it may underlie the Frank-Starling relationship (1), and is essential to flight in multiple orders of insects, which together comprise ∼75% of insect species (2) and fully half of all animal taxa (3). Since stretch activation was first reported by Pringle (4), a great deal has been learned about how muscular contraction is driven by cyclic myosin-actin interactions (5) which, in vertebrate skeletal muscles, are controlled by calcium's effect on the steric blocking action of troponin-tropomyosin (6). However, even atomic resolution models of myosin-actin (7) and the troponin complex (8, 9) fail to shed any light on the mechanism of activation by stretch. The central question of stretch activation remains: How does mechanical stress convert to myosinactin activation while the requisite [Ca 2þ ] stays constant?Recently we observed cross-bridges between thick (mainly myosin) filaments and thin (mainly actin-troponin-tropomyosin) filaments at the level of the troponin (10). These myosin-troponin connections, referred to here simply as troponin bridges, comprised about 15% of all cross-bridges identified in an insect flight muscle (IFM) quick frozen during an isometric contraction. Troponin bridges represent a newly recognized class of crossbridges, distinct from the "traditional" force-generating myosin cross-bridges that bind to actin target zones halfway between troponins in IFM (10, 11). The direct observation of troponin bridges revived a previously speculative mechanism for stretch activation (12), in which troponin bridges serve as the agent of mechanica...

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Section: At Physiological Temperatures (35-40°) Chemically Skinnedmentioning

confidence: 61%

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle

Edwards

Irving

Baumann

et al. 2010

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

108

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“…The position of TM is shifted on the actin filament in response to Ca 2ϩ binding to troponin (Tn) (1,2). According to current models of thin filament regulation of the actin-myosin interaction, Ca 2ϩ triggers contraction from a blocked thin filament state to a weak cross-bridge binding or closed state, and full activation requires an open state induced by strong crossbridge binding (3)(4)(5).…”

Section: ␣-Tropomyosin (␣-Tm)mentioning

confidence: 99%

Conserved Asp-137 Is Important for both Structure and Regulatory Functions of Cardiac α-Tropomyosin (α-TM) in a Novel Transgenic Mouse Model Expressing α-TM-D137L

Yar

Chowdhury

Davis

et al. 2013

Journal of Biological Chemistry

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Background: Conserved Asp-137 destabilizes the hydrophobic core of the coiled-coil tropomyosin. Results: Leu substitution of Asp-137 decreases flexibility of tropomyosin and causes long range structural rearrangements; mouse hearts expressing this variant show altered function. Conclusion: Residue Asp-137 is important for regulatory function of tropomyosin in the heart. Significance: Our data support the hypothesis that tropomyosin flexibility regulates cardiac function in vivo.

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“…At low Ca 2+ , Tm lies on SD1, where it sterically blocks the binding of myosin to actin (the "blocked" position); the consequent inhibition of actin-myosin interaction leads to muscle relaxation. On activation, Tn binds Ca 2+ , causing Tm to move onto actin SD3 (the "closed" position), exposing myosin binding sites on SD1 and initiating crossbridge cycling and contraction (29)(30)(31)(32)(33)(34)(35). When a model of Tm in its low Ca 2+ (blocked) state is positioned on the reconstruction of F-actin decorated with C0C3, it appears to clash with cMyBP-C's C0 and C1 domains, suggesting that cMyBP-C and Tm might compete for binding to SD1 in the relaxed thin filament (25,27,28).…”

mentioning

confidence: 99%

Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism

Mun

Previs

et al. 2014

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

133

207

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Significance Myosin-binding protein C (MyBP-C) is a component of myosin filaments, one of the two sets of contractile elements whose relative sliding is the basis of muscle contraction. In the heart, MyBP-C modulates contractility in response to cardiac stimulation; mutations in MyBP-C lead to cardiac disease. The mechanism by which MyBP-C modulates cardiac contraction is not understood. Using electron microscopy and a light microscopic assay for filament sliding, we demonstrate that MyBP-C binds to the other set of filaments, containing actin and the regulatory component, tropomyosin. In so doing, it displaces tropomyosin from its inhibitory position to activate actin filament interaction with myosin, promoting filament sliding. These findings provide insights into the molecular basis of heart function.

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X-Ray Evidence for a Conformational Change in the Actin-containing Filaments of Vertebrate Striated Muscle

Cited by 384 publications

References 0 publications

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle

Conserved Asp-137 Is Important for both Structure and Regulatory Functions of Cardiac α-Tropomyosin (α-TM) in a Novel Transgenic Mouse Model Expressing α-TM-D137L

Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism

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