A conserved mechanism of membrane fusion in nuclear pore complex assembly.
The nuclear pore complex (NPC) serves as the central transport gateway between nucleus and cytoplasm. NPC biogenesis requires the assembly of over 500 proteins culminating in the fusion of the inner and outer nuclear membranes. The mechanism of membrane fusion is unknown. Here, we elucidate how Brl1 and Brr6 mediate membrane fusion in S. cerevisiae. Our data suggest that both proteins form ring-shaped complexes with membrane-remodeling activity. Brl1 localizes to NPC assembly sites via a nuclear export sequence and interacts with Brr6 across the nuclear envelope through conserved hydrophobic loops. Disrupting this interaction blocks fusion and halts NPC assembly. Molecular dynamics simulations suggest that the Brl1-Brr6 complex drives membrane fusion by forming a channel across the bilayers enabling lipid exchange. Phylogenetic analyses and functional experiments in human cells and D. melanogaster establish CLCC1 as the NPC fusogen in metazoans. Together, our results uncover a conserved membrane fusion mechanism in eukaryotes.
Fischer JS, Wojtynek M, Kumar A, Baird H, Radilová K, Maslennikova D, Ramachandran K, Becker AN, Agote-Aran A, Loffreda A, Kralt A, Jagannathan M, Dey G, Kutay U, Vanni S, Weis K