Phosphoregulation of Tau modulates inhibition of kinesin-1 motility
Stern, J. L.
Lessard, D. V.
Hoeprich, G. J.
Morfini, G. A.
Berger, C. L.
PublisherAmerican Society for Cell Biology
MetadataShow full item record
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 partici- pate in signaling cascades, modulate microtubule dynamics, and preferentially inhibit kine- sin-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 phos- phorylation, 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 equilib- rium toward the dynamic state. We also present the first evidence of Tau’s static–dynamic state equilibrium under physiological conditions.