Tau is a structural microtubule-associated protein (MAP) predominantly (but not exclusively) localized to microtubules (MTs) within neuronal axons. Tau is arguably the most studied MAP, primarily due to its central role in neurodegenerative tauopathies (e.g., Alzheimer’s Disease, corticobasal degeneration, frontotemporal dementia)1,2. Importantly, tau is as essential in normal cellular physiology as in neurodegeneration. First described as a MAP which promotes assembly of MTs3-5, tau’s roles now also include MT stabilization, MT bundling, modulation of MT-dependent axonal transport, and regulation of neurite outgrowth1,2,6-10. However, the complete physiological understanding of how tau regulates MT functional organization remains unknown. Four recent studies of novel means by which tau interacts with MTs and other MAPs are discussed below.
Technological advances, especially in microscopy, provide unparalleled direct, single molecule insights into how tau binds MTs9-11. A recent cryo-electron microscopy study12 reveals that tau’s repeat MT binding regions adopt extended structures and bind to the MT surface along a protofilament to stabilize interactions between tubulin heterodimers (Fig. 1). The extended conformation of each repeat region spans intra- and interdimer interfaces, allowing connections between tubulin heterodimers12 (Fig. 1). These analyses at the near-atomic level have led some researchers10 to suggest that tau is ideally situated to promote MT assembly, perhaps in the absence of any stabilization given tau’s rapid on-off rate13. Tau’s rate was determined through fast single molecule tracking experiments. These findings contrast with the dogma that structural MAPs adhere to the MT surface in a static fashion to prevent disassembly. In living neuronally-derived cells and primary neurons, tau dynamically binds, dissociates, and binds neighboring MTs rapidly (termed “kiss and hop”) with an on-off rate of 40 milliseconds13. Despite this unexpectedly rapid MT dwell time (shorter by two orders of magnitude than previously reported14), tau was still a potent promoter of tubulin polymerization in neurites.
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