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Self-organization and cooperativity of cytoskeletal molecular motors

Any de lectura o publicació: 
2016
Autor/s: 
David Oriola Santandreu
Director/s o editor/s: 
Jaume Casademunt Viader

The present work deals with different aspects concerning the collective action of cytoskeletal molecular motors. The thesis is organized in two parts: the first part corresponds to the study of the cooperative action of molecular motors in intracellular transport, whereas the second part corresponds to the study of oscillatory dynamical instabilities driven by molecular motors. In the first part of the thesis, we carry out complete theoretical and experimental studies on the single-headed kinesin KIF1A, which constitutes a remarkable example of Brownian motor and a model motor to study intracellular transport. We provide a thorough numerical study of the collective action of single-headed KIF1A motors based on Brownian dynamics. We predict a dramatic improvement of the collective performance of these motors for tasks associated to the transport of membrane-bound cargoes. From a biological point of view, our results reinforce the hypothesis that the specificity of KIF1A to axonal vesicular trafficking is due to its unique adaptation to cooperative force generation. From a fundamental physics point of view, we show that Brownian motors based on two-state ratchets with independent switching and under unequal loading are remarkably adapted to cooperative force generation. We further test our predictions using a lattice model to study the dynamics of two interacting KIF1A motors. We show analytically the presence of cooperativity in the system and we consider a first extension of the problem to an arbitrary number of motors. Finally, we test our theoretical predictions experimentally, by using biomimetic tube pulling assays with single-headed KIF1A motors. We show that, despite the extreme inefficieny of the individual motors, they are able to cooperate collectively to extract membrane tubes, thus validating our theoretical predicitions. Additionally, we find the surprising formation of helical tubes around microtubules. This entails an impressive capability of single-headed KIF1A motors to exert significant off-axis by virtue of a diffusive state. Accordingly, this state affords two complementary strategies to overcome obstructions: brute force and manoeuvreing capability. In a series configuration (in line) it enables the generation of large forces by accumulation of motors, whereas in a parallel configuration (side by side) it enables lateral displacement of the cargo. In the second part of the thesis, we study the generation of dynamical instabilities driven by molecular motors. In particular, the spontaneous oscillations in a minimal in vitro actomyosin system and the self-organized flagellar beating driven by axonemal dynein. In the first case, we study theoretically an actomyosin system coupled to an elastic element, generating spontaneous oscillations in the presence of ATP via a Hopf bifurcation. This problem mimics the mechanism responsible of the asynchronous wing thrust observed in some insect species. We show that the theoretical model, based on an integro-differential system of equations, can be reduced to a simple three-dimensional ODE system. We find that both the complete and reduced systems exhibit subharmonic oscillations in some regimes. Remarkably, subharmonic peaks were reported experimentally in the signal power spectrum of a minimal in vitro actomyosin system. Hence, we provide an explanation for this phenomenon. In the second case, we study the nonlinear dynamics of axonemal beating driven by molecular motors. The explicit nonlinear equations for the flagellar shape and dynein kinetics are derived and solved numerically. Our analysis reveals the spatiotemporal dynamics of dynein kinetics and flagellum shape for different regimes of motor activity, medium viscosity and flagellum elasticity. We find that far from the bifurcation, linearized solutions fail to describe the flagellar shape and nonlinear effects arise in the system solely due to motor activity. Finally, we further characterize flagellar dynamics using principal component analysis and studying bending initiation

Idioma de la publicació: 
English