Structural dynamics and pH-regulated membrane binding of the TRAF2-NC trimer

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a key adaptor in TNF receptor-signaling that operates as a trimeric assembly. Here we investigate the structural and functional properties of a TRAF2 construct spanning the trimerization and receptor-binding domains (TRAF2-NC, residues 266-501). According to SAXS data, under physiological conditions, TRAF2-NC preserves a stable trimeric structure with signs of conformational flexibility. Conversely, in a mildly acidic environment (pH 5.7), the protein adopts a less compact and more heterogeneous conformation. In this condition, fluorescence energy transfer measurements reveal an increased membrane-binding propensity in the presence of ganglioside GM1. Together, these results indicate that TRAF2 oligomerization is modulated by pH-dependent conformational changes, suggesting that increased structural flexibility and partial exposure of hydrophobic regions facilitate membrane association under stress conditions, and providing a mechanistic link between structural dynamics and TRAF2 function.