Conformation of tau protein, the subunit of Alzheimer paired helical filaments, studied by solution X-ray scattering

Tau protein is a neuronal microtubule-associated protein. Its main role is to stabilize the microtubules in axons of nerve cells. This in turn enables microtubules to serve as tracks for intracellular transport of cellular cargoes from the cell body to the nerve terminals and back again. Examples are cell organelles (mitochondria, peroxisomes), vesicles containing proteins and lipids (such as synaptic vesicles and other types of vesicles), or protein complexes (e.g. components of receptors). Tau is a highly soluble protein, however, in brain diseases such as Alzheimer's disease tau becomes modified (mainly by phosphorylation at multiple sites) and aggregates into the pathologically "paired helical filaments" that are a hallmark of Alzheimer's and other neurodegenerative "tauopathies". In the adult human central nervous system, tau occurs mainly as 6 isoforms which are generated by alternative splicing from a single gene located on chromosome 17. In previous studies we have investigated the conformation of tau and its aggregation into fibers by biochemical and spectroscopic methods [1]. The results showed that tau is a prototype of a "natively unfolded protein" in which secondary structure elements such as αhelices and β-sheets are nearly absent. Nevertheless, the hydrodynamic behavior of tau shows that its structure is distinct from molten-globule or denatured states [2]. This suggests that there must be elements of folding which are retained in an otherwise "random chain" environment which may be responsible for the functions of tau, such as binding and stabilizing microtubules or the pathological function of aggregation into fibers [3].