The interaction of calmodulin (CaM) with the receptor for retinol uptake, STRA6, involves an α-helix termed BP2 that is located on the intracellular side of this homodimeric transporter (Chen et al., 2016 [1]). In the absence of Ca, NMR data showed that a peptide derived from BP2 bound to the C-terminal lobe (C-lobe) of Mg-bound CaM (CaM). Upon titration of Ca into CaM-BP2, NMR chemical shift perturbations (CSPs) were observed for residues in the C-lobe, including those in the EF-hand Ca-binding domains, EF3 and EF4 (K = 60 ± 7 nM). As higher concentrations of free Ca were achieved, CSPs occurred for residues in the N-terminal lobe (N-lobe) including those in EF1 and EF2 (K = 1000 ± 160 nM). Thermodynamic and kinetic Ca binding studies showed that BP2 addition increased the Ca-binding affinity of CaM and slowed its Ca dissociation rates (k) in both the C- and N-lobe EF-hand domains, respectively. These data are consistent with BP2 binding to the C-lobe of CaM at low free Ca concentrations (<100 nM) like those found at resting intracellular levels. As free Ca levels approach 1000 nM, which is typical inside a cell upon an intracellular Ca-signaling event, BP2 is shown here to interact with both the N- and C-lobes of Ca-loaded CaM (CaM-BP2). Because this structural rearrangement observed for the CaM-BP2 complex occurs as intracellular free Ca concentrations approach those typical of a Ca-signaling event (K = 1000 ± 160 nM), this conformational change could be relevant to vitamin A transport by full-length CaM-STRA6.