Competition between microtubule-associated proteins directs motor transport

Abstract

2 Within cells, numerous motor and non-motor microtubule-associated proteins (MAPs)simultaneously converge on the microtubule lattice. How the binding activities of nonmotor MAPs are coordinated and how they contribute to the balance and distribution of microtubule motor transport is unknown. Here, we examine the relationship between MAP7 and tau due to their antagonistic effects on neuronal branch formation and kinesin motility in vivo 1-8 . We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. In striking contrast to the inhibitory effect of tau, MAP7 promotes kinesin-based transport in vivo and strongly enhances kinesin-1 binding to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. In contrast, both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs exhibit differential control over distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of molecular motor activity.The balance of intracellular transport is essential for the structural and functional organization of a cell. The microtubule motors, kinesin-1 and cytoplasmic dynein, drive cellular cargoes towards microtubule plus-ends and minus ends, respectively. Mutations in either motor pathway disrupt the balance of transport and cause a range of diseases 9,10 . Motors must navigate a crowded microtubule lattice that is decorated with non-motor MAPs. These MAPs play various roles in regulating microtubule dynamics, turnover, and stability, as well as in influencing molecular motor transport 3,[11][12][13] . The Alzheimer's disease related MAP, tau (MAPT), is highly enriched in neuronal axons and inhibits kinesin-1 motility in vivo and in vitro, but has less of an effect on dynein-based movement [3][4][5][6][7][8] . How plus-end directed transport is accomplished in the tau-3 rich axonal environment is therefore an outstanding question, though the effects of tau on other classes of kinesin motors have not been tested. One MAP that appears to be antagonistic to tau is MAP7 ensconsin) 14,15 . The knockdown of MAP7 or tau in neurons produces opposite axonal branching phenotypes 1,2 . In addition, MAP7 is important for kinesin-based cargo transport and nuclear positioning in vivo [16][17][18] ; however, the molecular mechanism underlying this relationship is unclear. How tau and MAP7 activities are coordinated on the surface of individual microtubules in cells, and the functional consequence of MAP distributions on microtubule motor motility remain open questions.To approach this problem, we first examined the localization patterns of MAP7 and tau in mature Drosophila peripheral nervous system neurons in vivo and DIV4 primary mouse neuronal cultures. In both systems, we found that MAP7 localized within both dendrites and axons, while tau was predominantl...

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

“…How polyglutamylation regulates the transport of distinct axonal cargoes needs to be determined. The modification could either directly affect the efficiency of the molecular motors, such as kinesins and dynein (Ikegami et al, 2007;Sirajuddin et al, 2014), or alternatively affect the microtubule binding of other proteins that affect cargo transport (Kang et al, 2008;Barlan et al, 2013;Semenova et al, 2014;Monroy et al, 2018;Tymanskyj et al, 2018). Inefficient cargo transport could thus be one of the factors that lead to a progressive degeneration of neurons in the different mouse models we have described in this work.…”

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

“…In vivo, MAP7 interacts with kinesin-1 to regulate cell polarity in Drosophila oocytes, organelle transport in S2 cells, and nuclear positioning in both Drosophila and mammalian muscle cells (Sung et al, 2008;Metzger et al, 2012;Barlan et al, 2013). In vitro, MAP7 competes with another MAP, tau, and directly enhances kinesin-1 binding to the microtubule, but inhibits kinesin-3 from accessing the microtubule (Monroy et al, 2017). Recently, MAP7 was found to be up-regulated during collateral branch formation in dorsal root ganglion (DRG) neurons, and overexpression of MAP7 led to a dramatic increase in the number of collateral branches (Tymanskyj et al, 2017).…”

Golgi‐associated microtubules are fast cargo tracks and required for persistent cell migration

“…A number of MT properties can affect cargo behavior, including post-translational modifications (PTMs) [30,50], MT-associated protein (MAPs) [51,52], MT defects [31], and morphology of MTs and MT networks [29,36]. MT acetylation and detyrosination have been reported to promote kinesin-1 motility [30].…”