Switching Muscles On and Off in Steps: The McKillop-Geeves Three-State Model of Muscle Regulation

Lehman, William

doi:10.1016/j.bpj.2017.04.053

Cited by 29 publications

(18 citation statements)

References 55 publications

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“…In this work, we have shown that a change in the energy landscape profile for actin-tropomyosin interaction defined by the D292V actin mutation strengthens thin filament interactions. The altered landscape interferes with the dynamic regulatory transitions, and, in this case, the corresponding contractile system is trapped in an off-state, consistent with expectations of the McKillop-Geeves model (40).…”

Section: Perspectivesupporting

confidence: 80%

Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function

Rynkiewicz

Prum

Hollenberg

et al. 2017

Biophysical Journal

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Elongated tropomyosin, associated with actin-subunits along the surface of thin filaments, makes electrostatic interactions with clusters of conserved residues, K326, K328, and R147, on actin. The association is weak, permitting low-energy cost regulatory movement of tropomyosin across the filament during muscle activation. Interestingly, acidic D292 on actin, also evolutionarily conserved, lies adjacent to the three-residue cluster of basic amino acids and thus may moderate the combined local positive charge, diminishing tropomyosin-actin interaction and facilitating regulatory-switching. Indeed, charge neutralization of D292 is connected to muscle hypotonia in individuals with D292V actin mutations and linked to congenital fiber-type disproportion. Here, the D292V mutation may predispose tropomyosin-actin positioning to a myosin-blocking state, aberrantly favoring muscle relaxation, thus mimicking the low-Ca effect of troponin even in activated muscles. To test this hypothesis, interaction energetics and in vitro function of wild-type and D292V filaments were measured. Energy landscapes based on F-actin-tropomyosin models show the mutation localizes tropomyosin in a blocked-state position on actin defined by a deeper energy minimum, consistent with augmented steric-interference of actin-myosin binding. In addition, whereas myosin-dependent motility of troponin/tropomyosin-free D292V F-actin is normal, motility is dramatically inhibited after addition of tropomyosin to the mutant actin. Thus, D292V-induced blocked-state stabilization appears to disrupt the delicately poised energy balance governing thin filament regulation. Our results validate the premise that stereospecific but necessarily weak binding of tropomyosin to F-actin is required for effective thin filament function.

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Section: Perspectivesupporting

confidence: 80%

Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function

Rynkiewicz

Prum

Hollenberg

et al. 2017

Biophysical Journal

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“…This is an area that has begun to be tackled. Lehman and Orzechowsky have considered the regulatory conformational changes of the 'steric blocking' mechanism of actin-tropomyosin in terms of an energy landscape in which tropomyosin is located in a set of energy wells on the actin surface whose relative stability and energy barriers between states is dictated by the regulatory state (open, closed and blocked) controlled by troponin, Ca 2+ and myosin heads (Kiani et al 2018;Orzechowski et al 2014;Lehman 2017). Likewise, the troponin Ca 2+ -switch may be represented as a reaction coordinate where the probability and rates of progress between multiple states from inactive to active is determined by the Ca 2+ binding and the associated energy barriers (Dong et al 1999;Stevens et al 2017) (Fig.…”

Section: How the Ca 2+ Switch Work At The Atomic Levelmentioning

confidence: 99%

“…Overall these simulations indicate that phosphorylation stabilises the open state, in a similar way to that proposed by Barashnikov et al (2008a). The model derived from molecular dynamics offers an explanation as to how mutations could uncouple TnI phosphorylation from the change in Ca 2+ -sensitivity, a phenomenon seen with many HCM and DCM-related mutations (Memo et al 2013;Messer et al 2016;2017). Early studies indicate that mutations destabilise the open state (Zamora 2019).…”

Section: Modulation Of the Ca 2+ Switch By Troponin I Phosphorylationmentioning

confidence: 99%

Troponin structure and function: a view of recent progress

Marston

Zamora

2019

J Muscle Res Cell Motil

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The molecular mechanism by which Ca 2+ binding and phosphorylation regulate muscle contraction through Troponin is not yet fully understood. Revealing the differences between the relaxed and active structure of cTn, as well as the conformational changes that follow phosphorylation has remained a challenge for structural biologists over the years. Here we review the current understanding of how Ca 2+ , phosphorylation and disease-causing mutations affect the structure and dynamics of troponin to regulate the thin filament based on electron microscopy, X-ray diffraction, NMR and molecular dynamics methodologies.

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“…(Szent-Györgyi 1949). Key missing pieces of the functional regulation of muscle contraction were revealed by subsequent pioneering studies establishing the classic sliding filament and steric blocking theories (Huxley and Niedergerke 1954;Huxley and Hanson 1954;Huxley 1957;Huxley and Simmons 1971;Haselgrove and Huxley 1973;Parry and Squire 1973;McKillop and Geeves 1993;Lehman et al 1994;Lehrer and Geeves 1998;Geeves 2016;Lehman 2016Lehman , 2017.…”

Section: "To See Them Contract For the First Time" (Szent-györgyi 1963)mentioning

confidence: 99%

The discovery of actin: “to see what everyone else has seen, and to think what nobody has thought”*

Bugyi

Kellermayer

2019

J Muscle Res Cell Motil

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Actin is among the most highly abundant and ubiquitous proteins in eukaryotic cells. The structure, dynamics and functional diversity of actin have continued to mesmerise cell and molecular biologists, biophysicists and physiologists for more than three quarters of a century. The discovery and initial characterization of actin, which took place in the laboratory of Albert Szent-Györgyi by Ilona Banga and Brúnó F. Straub during the second world war in Hungary, is a remarkable and inspiring moment in the history of science. Many of the early thoughts and ideas on the properties and functions of actin and particularly actomyosin, which are referred to in this short historical overview, resonate freshly even today.

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Switching Muscles On and Off in Steps: The McKillop-Geeves Three-State Model of Muscle Regulation

Abstract: BJ Classic highlighting the article "Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament."

Cited by 29 publications

References 55 publications

Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function

Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function

Troponin structure and function: a view of recent progress

The discovery of actin: “to see what everyone else has seen, and to think what nobody has thought”*

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