Biological membranes are not just passive barriers—they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels; yet, how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 Å cryo-electron microscopy structure of the human stomatin complex in a native membrane environment. We find that stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a ∼12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits C16 symmetry, the C terminal domains adopt two alternating conformations, producing a symmetry-broken hydrophobic β-barrel pore with local C8 symmetry. The membrane beneath the complex remains flat despite surrounding curvature, indicating localized membrane stiffening. The structure reveals a conserved network of inter-subunit salt bridges that stabilize the assembly. These findings provide a molecular framework for how stomatin oligomers shape membrane architecture and mechanics, offering insight into their roles in mechanotransduction and diseases such as nephrotic syndrome.
Stoner et al. (Sun,) studied this question.