Timm T, Matenia D, Li X-Y, Griesshaber B, Mandelkow E-M
Max Planck Unit for Structural Molecular Biology, Hamburg, Germany.
Neurodegener Dis. 2006;3(4-5):207-17. doi: 10.1159/000095258.
The hyperphosphorylation of tau is an early step in the degeneration of neurons in Alzheimer's disease and other tauopathies. Of particular importance is the phosphorylation of tau in the repeat domain which detaches tau from microtubules. This makes microtubules dynamic for their role in differentiation and neurite outgrowth, and it controls the level of tau on the microtubule surface which keeps the tracks clear for axonal transport. However, the detachment of tau from microtubules can also initiate the reactions that lead to pathological aggregation into neurofibrillary tangles. Phosphorylation of tau in the repeat domain is achieved by the kinase MARK/Par-1, a member of the calcium/calmodulin-dependent protein kinase group of kinases. In this report, we focus on the modes of MARK regulation. MARK contains several domains which offer multiple ways of regulation by posttranslational modification (e.g. phosphorylation), interactions with scaffolding proteins and subcellular targeting (e.g. 14-3-3), and interactions with other proteins. We consider in particular the interactions between MARK and other kinases, notably MARKK/TAO-1 and PAK5. MARKK (a member of the Ste20 family of kinases) activates MARK by phosphorylating it at a critical threonine residue within the activation loop. Activated MARK in turn phosphorylates tau, causes its detachment from microtubules and renders them labile. PAK5 inactivates MARK, not by phosphorylation, but by binding to the catalytic domain. PAK5 contributes to microtubule stability by preventing the MARK-induced phosphorylation of tau; conversely, PAK5 contributes to actin dynamics, presumably through the activation of cofilin, an F-actin severing protein. Thus, MARK and its regulators MARKK and PAK5 appear to mediate the crosstalk between the actin and microtubule cytoskeleton in an antagonistic fashion.
tau蛋白的过度磷酸化是阿尔茨海默病和其他tau蛋白病中神经元退化的早期步骤。特别重要的是tau蛋白在重复结构域的磷酸化，这会使tau蛋白与微管分离。这使得微管在分化和神经突生长中发挥动态作用，并控制微管表面tau蛋白的水平，从而为轴突运输保持轨道畅通。然而，tau蛋白从微管上的分离也会引发导致病理性聚集形成神经原纤维缠结的反应。tau蛋白在重复结构域的磷酸化是由激酶MARK/Par-1完成的，它是钙/钙调蛋白依赖性蛋白激酶家族的成员。在本报告中，我们重点关注MARK的调节模式。MARK包含几个结构域，这些结构域通过翻译后修饰（如磷酸化）、与支架蛋白的相互作用和亚细胞靶向（如14-3-3）以及与其他蛋白的相互作用提供多种调节方式。我们特别考虑MARK与其他激酶之间的相互作用，尤其是MARKK/TAO-1和PAK5。MARKK（Ste20激酶家族的成员）通过在激活环内的关键苏氨酸残基处磷酸化来激活MARK。激活的MARK反过来磷酸化tau蛋白，使其从微管上分离并使其不稳定。PAK5不是通过磷酸化，而是通过与催化结构域结合来使MARK失活。PAK5通过阻止MARK诱导的tau蛋白磷酸化来促进微管稳定性；相反，PAK5可能通过激活丝切蛋白（一种F-肌动蛋白切断蛋白）来促进肌动蛋白动力学。因此，MARK及其调节因子MARKK和PAK5似乎以拮抗的方式介导肌动蛋白和微管细胞骨架之间的相互作用。
