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Sarcomeric pattern formation by actin cluster coalescence.

Friedrich BM, Fischer-Friedrich E, Gov NS, Safran SA - PLoS Comput. Biol. (2012)

Bottom Line: Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments.In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation.The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de

ABSTRACT
Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

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Actin filament length control by severing.A. Filament severing provides a simple physical mechanism for actin filament length control, see main text. In an idealized scenario, an actin filament (blue) binds a severing agent (scissors) with a rate  that is proportional to its length  at a random position. The filament is then cut at the binding position, and its minus-end facing fragment is subsequently depolymerized. B. Actin filament severing results in a unimodular filament length distribution at steady state, see histrogram (gray) and analytical expression (red, see SI text S1). For the severing rate used, , mean filament length , and filament length variability parameter, . C. Simulation of an acto-myosin bundle as in figure 3, but with actin filament severing as described in panel A. Shown is a snap-shot of the simulations at time  (actin filaments: blue and red; myosin: magenta; end-tracking crosslinker: green), as well as the averaged structure factor (black curve, gray region indicates means.e., ).
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pcbi-1002544-g006: Actin filament length control by severing.A. Filament severing provides a simple physical mechanism for actin filament length control, see main text. In an idealized scenario, an actin filament (blue) binds a severing agent (scissors) with a rate that is proportional to its length at a random position. The filament is then cut at the binding position, and its minus-end facing fragment is subsequently depolymerized. B. Actin filament severing results in a unimodular filament length distribution at steady state, see histrogram (gray) and analytical expression (red, see SI text S1). For the severing rate used, , mean filament length , and filament length variability parameter, . C. Simulation of an acto-myosin bundle as in figure 3, but with actin filament severing as described in panel A. Shown is a snap-shot of the simulations at time (actin filaments: blue and red; myosin: magenta; end-tracking crosslinker: green), as well as the averaged structure factor (black curve, gray region indicates means.e., ).

Mentions: Our simulations suggest that sarcomere spacing is set by the length of actin filaments at early stages of striated ordering. How is actin filament length controlled within a pool of highly dynamic actin filaments? Capping proteins regulate filament polymerization and depolymerization rates. However, on their own, these proteins do not provide a means to tune the average filament length to a set point since they act locally in a manner that is not sensitive to the total length of a filament. Energetically favorable crosslinking or attraction of actin filaments all along their length can result in a unimodular length distribution as this ensures maximal mutual overlap of filaments [47]. However, to allow for filament sliding and sorting, such crosslinking would have to be highly dynamic. Alternatively, severing agents (such as ADF/cofilin-like UNC-60B [23]) are recruited by actin filaments in a length-dependent manner and can provide a generic feedback mechanism that controls actin filament length [48]–[50]. We consider a simple implementation of actin filament severing assuming that filaments elongate by polymerization at their plus-end with constant polymerization speed , whereas the minus-end is stable. A generic severing agent can bind with constant rate anywhere along the filament and cut it there. Since the minus-end facing fragment of a cut actin filament comprises mainly ADP-bound actin monomers and thus is less stable, we assume that this fragment rapidly depolymerizes after severing, see figure 6A.


Sarcomeric pattern formation by actin cluster coalescence.

Friedrich BM, Fischer-Friedrich E, Gov NS, Safran SA - PLoS Comput. Biol. (2012)

Actin filament length control by severing.A. Filament severing provides a simple physical mechanism for actin filament length control, see main text. In an idealized scenario, an actin filament (blue) binds a severing agent (scissors) with a rate  that is proportional to its length  at a random position. The filament is then cut at the binding position, and its minus-end facing fragment is subsequently depolymerized. B. Actin filament severing results in a unimodular filament length distribution at steady state, see histrogram (gray) and analytical expression (red, see SI text S1). For the severing rate used, , mean filament length , and filament length variability parameter, . C. Simulation of an acto-myosin bundle as in figure 3, but with actin filament severing as described in panel A. Shown is a snap-shot of the simulations at time  (actin filaments: blue and red; myosin: magenta; end-tracking crosslinker: green), as well as the averaged structure factor (black curve, gray region indicates means.e., ).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369942&req=5

pcbi-1002544-g006: Actin filament length control by severing.A. Filament severing provides a simple physical mechanism for actin filament length control, see main text. In an idealized scenario, an actin filament (blue) binds a severing agent (scissors) with a rate that is proportional to its length at a random position. The filament is then cut at the binding position, and its minus-end facing fragment is subsequently depolymerized. B. Actin filament severing results in a unimodular filament length distribution at steady state, see histrogram (gray) and analytical expression (red, see SI text S1). For the severing rate used, , mean filament length , and filament length variability parameter, . C. Simulation of an acto-myosin bundle as in figure 3, but with actin filament severing as described in panel A. Shown is a snap-shot of the simulations at time (actin filaments: blue and red; myosin: magenta; end-tracking crosslinker: green), as well as the averaged structure factor (black curve, gray region indicates means.e., ).
Mentions: Our simulations suggest that sarcomere spacing is set by the length of actin filaments at early stages of striated ordering. How is actin filament length controlled within a pool of highly dynamic actin filaments? Capping proteins regulate filament polymerization and depolymerization rates. However, on their own, these proteins do not provide a means to tune the average filament length to a set point since they act locally in a manner that is not sensitive to the total length of a filament. Energetically favorable crosslinking or attraction of actin filaments all along their length can result in a unimodular length distribution as this ensures maximal mutual overlap of filaments [47]. However, to allow for filament sliding and sorting, such crosslinking would have to be highly dynamic. Alternatively, severing agents (such as ADF/cofilin-like UNC-60B [23]) are recruited by actin filaments in a length-dependent manner and can provide a generic feedback mechanism that controls actin filament length [48]–[50]. We consider a simple implementation of actin filament severing assuming that filaments elongate by polymerization at their plus-end with constant polymerization speed , whereas the minus-end is stable. A generic severing agent can bind with constant rate anywhere along the filament and cut it there. Since the minus-end facing fragment of a cut actin filament comprises mainly ADP-bound actin monomers and thus is less stable, we assume that this fragment rapidly depolymerizes after severing, see figure 6A.

Bottom Line: Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments.In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation.The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de

ABSTRACT
Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

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