Phosphoregulation of Tau modulates inhibition of kinesin-1 motility.
Phosphoregulation of Tau modulates inhibition of kinesin-1 motility.
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DOI：
10.1091/mbc.e16-10-0728
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发表时间：
2017-04-15
影响因子：
3.3
通讯作者：
Berger CL
中科院分区：
文献类型：
--
作者：
Stern JL;Lessard DV;Hoeprich GJ;Morfini GA;Berger CL
Regulation of axonal transport includes control of the microtubule-associated protein Tau. Site-specific pseudophosphorylation of Tau modulates its ability to inhibit kinesin-1 motility by both shifting its static–dynamic state binding equilibrium toward the dynamic state and reducing its affinity for microtubules. Microtubule-based axonal transport is tightly regulated by numerous pathways, ensuring appropriate delivery of specific organelle cargoes to selected subcellular domains. Highlighting the importance of this process, pathological evidence has linked alterations in these pathways to the pathogenesis of several neurodegenerative diseases. An important regulator of this system, the microtubule-associated protein Tau, has been shown to participate in signaling cascades, modulate microtubule dynamics, and preferentially inhibit kinesin-1 motility. However, the cellular means of regulating Tau’s inhibition of kinesin-1 motility remains unknown. Tau is subject to various posttranslational modifications, including phosphorylation, but whether phosphorylation regulates Tau on the microtubule surface has not been addressed. It has been shown that tyrosine 18 phosphorylated Tau regulates inhibition of axonal transport in the disease state. Tyrosine 18 is both a disease- and nondisease-state modification and is therefore an attractive starting point for understanding control of Tau’s inhibition of kinesin-1 motility. We show that pseudophosphorylation of tyrosine 18 reduces 3RS-Tau’s inhibition of kinesin-1 motility. In addition, we show that introduction of negative charge at tyrosine 18 shifts Tau’s previously described static–dynamic state binding equilibrium toward the dynamic state. We also present the first evidence of Tau’s static–dynamic state equilibrium under physiological conditions.
