S100A5 is a calcium-binding protein that belongs to the S100 family and exhibits dual roles in cellular signaling and cancer biology. The protein binds calcium ions sequentially with dissociation constants of 1.3 μM and 3.5 μM at its C-terminal and N-terminal EF-hands, respectively 1. S100A5 can simultaneously bind calcium, copper, and zinc ions, with calcium and copper competing for the same binding sites 2. Upon calcium binding, S100A5 undergoes conformational changes involving hinge loop rearrangement and helix reorientation, enabling interaction with target proteins 3. A major binding partner is the receptor for advanced glycation end products (RAGE), where calcium-bound S100A5 forms a heterotrimer with RAGE's V domain (KD ~5.9 μM) 1. In cancer biology, S100A5 functions as an immunosuppressive factor in bladder cancer by inhibiting CD8+ T cell recruitment, proliferation, and cytotoxicity through decreased pro-inflammatory chemokine secretion 4. This creates a non-inflamed tumor microenvironment that reduces immunotherapy efficacy. In meningiomas, S100A5 serves as a prognostic marker, where low expression correlates with higher recurrence risk in WHO grade I tumors 5. The protein's interaction with RAGE can be therapeutically targeted, as pentamidine blocks S100A5-RAGE binding by competing for the same binding region 6.