ALS-causing P56S mutation and splicing variation on the hVAPB MSP domain transform its β-sandwich fold into lipid-interacting helical conformations.

P56S mutation on VAPB MSP domain causes a familial ALS, characteristic of severe aggregation both in vivo and in vitro. We previously showed that P56S rendered the MSP domain to be predominantly disordered in water. Unexpectedly, here we reveal that P56S-MSP transforms into a highly helical conformation in a membrane environment. This chameleon transformation is shared by a splicing variant VAPB-3 with a truncated MSP domain, which is also highly disordered and buffer insoluble as demonstrated here by NMR. Our discovery provides a mechanism for ALS-causing VAPB mutants/variants to gain novel functions such as to mediate ER structure before significant accumulation of aggregates occurs.