RT Journal Article SR Electronic T1 Nano-particles carried by multiple dynein motors: A Self-Regulating Nano-Machine JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.07.09.194720 DO 10.1101/2020.07.09.194720 A1 I. Fayer A1 G. Halbi A1 D. Aranovich A1 S. Gat A1 S. Bar A1 V. Erukhimovitch A1 Rony Granek A1 Anne Bernheim-Groswasser YR 2020 UL http://biorxiv.org/content/early/2020/07/09/2020.07.09.194720.abstract AB Native cargos achieve efficient intra-cellular active transport by recruiting multiple motors proteins from the cytoplasm. Here we investigate the motion of spherical nano-particles (NPs) – acting as model cargos – grafted with flexible polymers, each ending with a nuclear localization signal (NLS) peptide, thereby allowing recruitment of mammalian cytoplasmic dynein. Bead-motility assays show several unique features. As the number of motors increases, the run-time and run-length increase, the longitudinal velocity mean decreases, whereas its width shows a non-monotonous behavior. Moreover, both single and multi-motor NPs perform angular (i.e., projected transverse) motion. Strikingly, the directions of angular and longitudinal motions are correlated, such that retrograde steps are combined with right-handed motion. We formulate a theoretical model to simulate the multi-dynein transported NP. The model builds on a recently theoretical description of single yeast dynein stepping on the curved microtubule surface, modified to account for mammalian dynein, and generalized to include motor-motor elastic and excluded-volume coupling. The simulation results are majorly in agreement with our experimental results. Moreover, long time trajectories exhibit both left- and right-handed helical motion around the MT symmetry axis, consistent with the measured and simulated angular velocity. The model gives further insight into the mechanism of the NP motion and suggests that the NPs are self-regulating the number of participating motors, optimizing between single motor, for obstacle bypassing, and multimotor behavior, for persistent directional motion. We suggest that native cargos could use a similar mechanism to achieve efficient transport in the crowded cellular environment.Significance Statement The mechanism of active transport of native cargos, such as HIV, is a long-standing conundrum. Their need for persistence motion towards the nucleus, while bypassing obstacles in the super-crowded intracellular milieu, requires sophisticated natural design. To fathom this machinery, we study a smartly designed nano-particle that recruits several dynein motor-proteins from the cytoplasm. Motility assays and model simulations reveal long run-times, long run-lengths, and helical motion around the microtubule symmetry axis. Moreover, the nano-particles self-regulate the number of dyneins participating in the motion, which optimizes its motility properties. We suggest that alternating between single motor motility, which is beneficial for obstacle bypassing, and multiple motor states, which engender persistent motion towards the nucleus, the NP achieves optimal transport efficiency.Competing Interest StatementThe authors have declared no competing interest.