The amyloidogenic C-terminal region of TMEM106B modulates lipid membrane biophysical properties: Functional and...

The lysosomal transmembrane protein 106B (TMEM106B) forms amyloid filaments in the human brain in an age-dependent manner, observed both in neurologically healthy individuals and in patients with neurodegenerative diseases also containing tau, α-synuclein, or TDP-43 inclusions. Despite its pathological and physiological relevance, the biochemical mechanisms governing TMEM106B structural stability and its functional interactions with membranes remain largely unknown. Here, we examined the luminal C-terminal fragment of TMEM106B (called TST, residues 120-254), corresponding to the amyloid fibril core identified by cryo-electron microscopy, to elucidate its functional membrane-binding properties. Using static solid-state ³¹P and ²H NMR in combination with magic-angle spinning ¹³C NMR, we characterized TMEM106B(120-254) interaction with multilamellar vesicles of varying lipid composition that mimic lysosomal membranes. TST binds peripherally to lipid bilayers and remodels their fluidity and elasticity in a composition-dependent manner. ³¹P NMR spectra revealed reduced chemical shift anisotropy and increased asymmetry, accompanied by an isotropic component indicative of enhanced headgroup motion and local curvature. Complementary ²H NMR spectra of POPC-d₃₁ showed decreased quadrupolar splittings and order parameters, demonstrating reduced acyl chain order upon TST binding. These effects were most pronounced in membranes containing anionic lipids and lacking cholesterol, suggesting that electrostatic interactions and lipid motion modulate the balance between random coil mobile TMEM106B and membrane-immobilized β-rich TMEM106B at the bilayer surface. Together, these findings identify TST as a surface-active remodeler that perturbs membrane structure without deep insertion, providing new insights into the membrane coupling mechanisms of TMEM106B and their potential implications for lysosomal physiology and amyloid formation.