biostudies-literatureUnknown9(1)Mendez-Ruette MThe soluble N-ethylmaleimide-sensitive factor attachment protein alpha (α-SNAP) is essential for vesicle trafficking, coordinating trans-SNARE zippering and cis-SNARE disassembly. α-SNAP also regulates autophagy, apoptosis, calcium signaling, and AMPK activity. The hyh missense mutation M105I produces a distinctive neurodevelopmental phenotype, yet its pathogenic mechanism remains unclear. Because many α-SNAP functions rely on lipid binding, we examined whether M105I alters this property. In silico modeling revealed structural rearrangements that conceal the N-terminal hydrophobic loop, and molecular dynamics simulations predicted reduced binding free energy and weakened protein-lipid interactions. These predictions were validated in vitro and in hyh mouse brains, showing diminished membraCommunications biology294https://www.ebi.ac.uk/biostudies/studies/S-EPMC12923601biostudies-literatureA pathogenic mutation in α-SNAP impairs membrane lipid binding by concealing a critical hydrophobic loop.PMC12923601Gonzalez WBrauchi SMendez-Ruette MMichaut MAVivar JPSandoval SBatiz LFMunoz-Gutierrez CParga CHenzi RHinrichsen BMunoz RIWyneken URoss BHMunoz CMardones GABedoya MMarquez GfalseA pathogenic mutation in α-SNAP impairs membrane lipid binding by concealing a critical hydrophobic loop.The soluble N-ethylmaleimide-sensitive factor attachment protein alpha (α-SNAP) is essential for vesicle trafficking, coordinating trans-SNARE zippering and cis-SNARE disassembly. α-SNAP also regulates autophagy, apoptosis, calcium signaling, and AMPK activity. The hyh missense mutation M105I produces a distinctive neurodevelopmental phenotype, yet its pathogenic mechanism remains unclear. Because many α-SNAP functions rely on lipid binding, we examined whether M105I alters this property. In silico modeling revealed structural rearrangements that conceal the N-terminal hydrophobic loop, and molecular dynamics simulations predicted reduced binding free energy and weakened protein-lipid interactions. These predictions were validated in vitro and in hyh mouse brains, showing diminished membra2026-01-01T00:00:00Z2026 Jan2026-07-16T14:44:20.427Z2026-07-09T11:00:31.578ZS-EPMC129236014156599510.1038/s42003-026-09578-y