The C-Terminal Tail of Human Neuronal Calcium Sensor 1 Regulates the Conformational Stability of the Ca2+-Activated State

Neuronal calcium sensor 1 (NCS-1) and orthologs are expressed in all organisms from yeast to humans. In the latter, NCS-1 plays an important role in neurotransmitter release and interacts with a plethora of binding partners mostly through a large solvent-exposed hydrophobic crevice. The structural basis behind the multispecific binding profile is not understood. To begin to address this, we applied NMR spectroscopy to determine the solution structure of calcium-bound human NCS-1. The structure in solution demonstrates interdomain flexibility and, in the absence of a binding partner, the C-terminal tail residues occupy the hydrophobic crevice as a ligand mimic. A variant with a C-terminal tail deletion shows lack of a defined structure but maintained cooperative unfolding and dramatically reduced global stability. The results suggest that the C-terminal tail is important for regulating the conformational stability of the Ca2+-activated state. Furthermore, a single amino acid mutation that was recently diagnosed in a patient with autistic spectrum disorder was seen to affect the C-terminal tail and binding crevice in NCS-1. [Display omitted] ► NCS-1 is important in neurotransmitter release. ► We solved the structure of nonmyristoylated calcium-loaded human NCS-1 by NMR spectroscopy. ► The C-terminal tail occupies the hydrophobic ligand binding crevice. ► The tail is detrimental to conformational integrity. ► The C-terminal tail may act as a ligand mimic.