Calcium ions modulate the structure of the intrinsically disordered Nucleobindin-2 protein.

Nucleobindin-2 (Nucb2) is a widely expressed multi-domain protein. Nucb2 participates in many physiological processes, i.e. calcium level maintenance, feeding regulation in the hypothalamus, emotion and stress regulation, and many others. To date, this protein has not been structurally characterized. We describe the first comparative structural analysis of two homologs, a Gallus gallus and a Homo sapiens Nucb2. The in silico analysis suggested that apo-Nucb2s contain a mosaic-like structure, consisting of intertwined disordered and ordered regions. Surprisingly, the hydrogen-deuterium exchange mass spectrometry results revealed that Nucb2 is divided into two parts: an N-terminal half with a stable mosaic-like structure and a disordered C-terminal half. However, the presence of Ca(2+) induces the formation of a mosaic-like structure in the C-terminal half of the Nucb2s. The Ca(2+) also affects the tertiary and quaternary structure of Nucb2s. The presence of Ca(2+) leads to an overall compaction of the Nucb2 molecule, resulting in structural change that is propagated along the molecule, which in turn affects the quaternary structure of the protein. Intrinsic disorder, and the mosaic-like Ca(2+) dependent structure of Nucb2s, might be seen as the molecular factors responsible for their multifunctionality. Thus, Nucb2s might function as the versatile Ca(2+) sensor involved in signal transduction.