Human calumenin 1 (HsCalu1) is an endoplasmic reticulum (ER) resident and secretory Ca2+-binding protein that belongs to the CREC superfamily. HsCalu1 acts as a Ca2+ sensor protein and plays an important role in regulating calcium-dependent processes within the ER. HsCalu1 is involved in protein sorting and regulates the function of vitamin K-dependent enzymes (vitamin K epoxide reductase and γ-carboxylase activity). Interaction of HsCalu1 with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) regulates the Ca2+ release activity from the cytosol. In this study, we demonstrate that HsCalu-1 acts as a chaperone both in its intrinsically disordered state (apo form) and the structured state (Ca2+-bound form). HsCalu-1 chaperone activity is independent of Ca2+ and Pb2+ binding attenuates its chaperone-like activity. Incidentally, Pb2+ binds to HsCalu-1 with lower affinity (KD = 38.46 μM) (compared to Ca2+-binding) leading to the formation of a less stable conformation as observed by a sharp drop in its melting temperature Tm from 67 ℃ in the Ca2+-bound form to 43℃ (in the presence of Pb2+). The binding site for Pb2+ was mapped as being in the EF-Hand-234 domain of HsCalu-1, a region that overlaps with the Ca2+-dependent initiator of its functional fold. A change in secondary and tertiary structure, leading to a less stable but compact conformation upon Pb2+ binding is the mechanism by which chaperone-like activity of HsCalu-1 is diminished. In addition, we found out that pH-dependent structural transition at pH 4 from random coil-like structure to β-sheets like conformation of HsCalu-1.