A model for tau polymerization

  Our in vitro studies have led us to a model of tau association with itself and other molecules that depends on its molecular conformation (figure below). Our model is based on the interaction of the microtubule binding repeat (MTBR) domain with the microtubule, with other parts of the same tau molecule, and with other tau molecules. In this model, tau is normally bound to the microtubule via the MTBRs (below center), and this binding precludes interaction of the MTBRs with either the amino or carboxy termini of the tau molecule. We hypothesize that when tau dissociates from the microtubule, the carboxy terminus interacts with the MTBRs to prevent self-association (below left; see also Role of the carboxy terminus). We further hypothesize that this conformation is in competition with an alternative occupation of the MTBRs by the amino terminus (below right; see also Role of the amino terminus). In this conformation, the MTBRs are free to form intermolecular interactions with those of other tau molecules, resulting in the assembly of tau filaments. In this model, association of the amino and carboxy termini with the MTBR domain is driven by electrostatic and hydrophobic interactions, respectively. Our model predicts that tau neuropathology leading to neurodegeneration results from cellular events that promote interaction of the MTBRs with the amino terminus. These would include those that directly involve the amino portion of the molecule, such as the R5L mutation (Role of the amino terminus), but would also include those that prevent the competitive interaction with the carboxy terminus, such as phosphorylation or proteolytic truncation (see also Post-translational modifications, and Role of the carboxy terminus, and Caspase cleavage).