Stomatin organizes laterally segregated membrane microdomains to modulate transmembrane transport and signal transduction

Stomatin is a member of the SPFH (Stomatin, Prohibitin, Flotillin, and HflK/C) protein family, and has been proposed to scaffold functional membrane microdomains (FMMs) on the plasma membrane. Functionally, stomatin has been reported to associate with diverse partner proteins and is implicated in various cellular processes. However, the mechanisms by which it organizes FMMs and exerts its regulatory roles remain unclear. Here, we characterize cryo-EM structures of the stomatin complex, revealing a hexadecameric membrane-anchored assembly that resembles an inverted cup. Sixteen SPFH1 domains insert into the cytosolic leaflet, defining an isolated circular membrane microdomain. Proteomic analyses reveal numerous proteins associated with stomatin, including solute carrier transporters, Rab GTPases and integrins. We further show that stomatin oligomerization is required for integrin-regulated directional cell migration. Together, these findings provide a foundation for understanding the basic role of stomatin in FMM organization and its versatile functions in various physiological and pathological processes. Stomatin is thought to scaffold functional membrane microdomains; but how it works remains unclear. Here, authors reveal its 16-mer structure, identify cargo proteins, and show that the integrity of its cup-like complex is crucial for cell migration