Oligomerization of VAP-B(P56S) prevents binding of FFAT proteins. We found that the conformational changes of MSP domain of P56S mutant have no direct effect on FFAT-binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and the transmembrane domains, thereby preventing accessibility to FFAT-binding site, facilitating the production of VAP-B(P56S) insoluble aggregates and consequently its neurotoxicity.
