Understanding the mechanism by which tau binds to and promotes microtubule (MT) assembly as part of its native function may also provide insight into its loss of function that occurs in neurodegenerative disease. Both mechanistic and structural studies of tau have been hindered by its intrinsic disorder and highly dynamic nature. Here, we combine fluorescence correlation spectroscopy and acrylodan fluorescence screening to study the stoichiometry and structural features of tau-tubulin assemblies. Our results show that tau binds to multiple tubulin dimers, even when MT assembly is inhibited. Moreover, we observe helical structure in the repeat regions of the MT binding domain of tau in the tau-tubulin complex, reflecting partial folding upon binding. Our findings support a role for tau's intrinsic disorder in providing a flexible scaffold for binding tubulin and MTs and a disorder-to-order transition in mediating this important interaction.
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