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

► P56S mutation in the VAPB MSP domain leads to a familial ALS. ► A recent study showed that the P56S mutant has a unique ability to remodel ER cisternae. ► Here, P56S-MSP/VAPB-3 was characterized to transform into helical conformations in membrane. ► We characterized VAPB-3 to be also buffer-insoluble but predominantly-disordered in water. ► Our results imply potential mechanisms underlying both sporadic and familial ALS.