The nucleotide-binding state of microtubules modulates kinesin processivity and the ability of Tau to inhibit kinesin-mediated transport.
The ability of Tau to act as a potent inhibitor of kinesin's processive run length in vitro suggests that it may actively participate in the regulation of axonal transport in vivo. However, it remains unclear how kinesin-based transport could then proceed effectively in neurons, where Tau is expressed at high levels. One potential explanation is that Tau, a conformationally dynamic protein, has multiple modes of interaction with the microtubule, not all of which inhibit kinesin's processive run length. Previous studies support the hypothesis that Tau has at least two modes of interaction with microtubules, but the mechanisms by which Tau adopts these different conformations and their functional consequences have not been investigated previously. In the present study, we have used single molecule imaging techniques to demonstrate that Tau inhibits kinesin's processive run length in an isoform-dependent manner on GDP-microtubules stabilized with either paclitaxel or glycerol/DMSO but not guanosine-5'-((α,β)-methyleno)triphosphate (GMPCPP)-stabilized microtubules. Furthermore, the order of Tau addition to microtubules before or after polymerization has no effect on the ability of Tau to modulate kinesin motility regardless of the stabilizing agent used. Finally, the processive run length of kinesin is reduced on GMPCPP-microtubules relative to GDP-microtubules, and kinesin's velocity is enhanced in the presence of 4-repeat long Tau but not the 3-repeat short isoform. These results shed new light on the potential role of Tau in the regulation of axonal transport, which is more complex than previously recognized.
Cell and Molecular Biology Program, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Derrick P
DP
McVicker
Lynn R
LR
Chrin
Christopher L
CL
Berger
D001692:Biological Transport / Q000187:drug effects; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D009711:Nucleotides; D020033:Protein Isoforms; D050257:Tubulin Modulators; D016875:tau Proteins; D016547:Kinesins; D017239:Paclitaxel