Structural basis for membrane remodelling by the AP5:SPG11-SPG15 complex

The human spastizin (spastic paraplegia 15, SPG15) and spatacsin (spastic paraplegia 11, SPG11) complex is involved in the formation of lysosomes, and mutations in these two proteins are linked with hereditary autosomal recessive spastic paraplegia (HSP). SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes. We employed cryo-electron microscopy and in silico predictions to investigate the structural assemblies of SPG11-SPG15 and AP5:SPG11-SPG15 complex. The W-shaped SPG11-SPG15 intertwined in a head-to-head fashion, and the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. The AP5 complex is in a super open conformation. Our findings reveal that the AP5:SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodelling in vitro. These studies provide key insights into the structure and function of the spastic paraplegia AP5:SPG11-SPG15 complex, which is essential for the initiation of autolysosome tubulation.