Castle Brian T, McKibben Kristen M, Rhoades Elizabeth, Odde David J
Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
iScience. 2020 Nov 6;23(12):101782. doi: 10.1016/j.isci.2020.101782. eCollection 2020 Dec 18.
Plus-end tracking proteins (+TIPs) associate with the growing end of microtubules and mediate important cellular functions. The majority of +TIPs are directed to the plus-end through a family of end-binding proteins (EBs), which preferentially bind the stabilizing cap of GTP-tubulin present during microtubule growth. One outstanding question is whether there may exist other microtubule-associated proteins (MAPs) that preferentially bind specific nucleotide states of tubulin. Here, we report that the neuronal MAP tau preferentially binds GDP-tubulin ( = 0.26 μM) over GMPCPP-tubulin ( = 1.1 μM) as well as GTP-tubulin at the tips of growing microtubules, causing tau binding to lag behind the plus-end both and in live cells. Thus, tau is a microtubule tip avoiding protein, establishing the framework for a possible new class of tip avoiding MAPs. We speculate that disease-relevant tau mutations may exert their phenotype by their failure to properly recognize GDP-tubulin.
正端追踪蛋白（+TIPs）与微管的生长末端相关联，并介导重要的细胞功能。大多数+TIPs通过一类末端结合蛋白（EBs）被导向微管正端，这类蛋白优先结合微管生长过程中存在的GTP-微管蛋白的稳定帽。一个突出的问题是，是否可能存在其他优先结合微管蛋白特定核苷酸状态的微管相关蛋白（MAPs）。在此，我们报告神经元MAP tau优先结合GDP-微管蛋白（解离常数=0.26μM）而非GMPCPP-微管蛋白（解离常数=1.1μM）以及生长中微管末端的GTP-微管蛋白，导致tau的结合在体外和活细胞中均落后于正端。因此，tau是一种避免微管末端结合的蛋白，为可能的新型避免末端结合MAPs建立了框架。我们推测与疾病相关的tau突变可能因其无法正确识别GDP-微管蛋白而发挥其表型作用。
