Figure 8

Schematic representation of AChE binding to PrP amyloid fibrils. This model of AChE interaction within PrP fibrils was built using full-length PrP and its deletion variants, and is based on the data on Hup8TH inhibition of aggregation. We considered that each PrP proto-filament consisted of an inner spine and an outer non-structured region that includes approximately the N-terminus and the first α-helix of PrP. Due to the specific structural features of the dimeric AChE molecule and the supposed regular structure of the PrP fibril, each AChE catalytic subunit (AChEcsub) in the dimer may only interact with a non-contiguous PrP protomer in the protofilament. Thus, in the case of full-length PrP fibrils, AChEcsub may associate with adjacent PrP protomers by alternately interacting with the N-terminal sites within residues 23 and 99 (in blue) and residues 100 and 120 (in red). As AChE binding to both sites in the same PrP protomer appears to be mutually exclusive, an equimolar interaction between proteins is therefore obtained. Conversely, for fibrils formed from truncated N-terminal PrP variants (∆100-120 and ∆23-99), which are characterized by the loss of one of the AChE binding sites, only alternate PrP protomers may be complexed with AChE. N-terminal steric hindrance between adjacent PrP protomers thus leads to a 0.5:1 stoichiometry. The inhibition data using Hup8TH are in agreement with the proposed model and reveal that the two PrP N-terminal sites have similar binding mechanisms, but different avidities. The number (n) of AChEcsub (associated and free) and PrP protomers is also shown. Further details are specified in the Discussion section.