The transmembrane protein TSPAN7 senses high membrane curvature and self-assembles into helical spiral structures on tubular membrane protrusions, forming a 'transmembrane skeleton' that mechanically stabilizes these fragile structures against shear stress-induced deformation through two critical molecular interaction interfaces (glutamate 115 and helix 2) that enable head-to-head and back-to-back polymerization into right-handed spirals composed of seven protofilaments.

Tubular cell membrane protrusions, such as filopodia, dendrites, tunneling nanotubes (TNTs) and retraction fibers, are prevalent on the cell surface. They play crucial roles in various physiological processes and disease states, including angiogenesis, wound healing, and cancer metastasis. The shaping and stabilization of these protrusions are crucial for their function, and the molecular machineries involved have long been an active area of investigation. Here we employed an integrative approach combining live-cell imaging, in vitro reconstitution, and in situ cryo-EM analysis to reveal that the transmembrane protein tetraspanin 7 (TSPAN7) senses membrane curvature and polymerizes into a helical configuration on highly curved tubular membranes. These spirals act as a “transmembrane skeleton”, effectively maintaining the structural integrity of membrane protrusions under mechanical stress. Our findings reveal a previously unreported assembly strategy for transmembrane proteins and a mechanism for maintaining tubular membrane protrusions.