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 Ca(2+)-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.
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark.
Pétur O
PO
Heidarsson
Ida J
IJ
Bjerrum-Bohr
Gitte A
GA
Jensen
Olaf
O
Pongs
Bryan E
BE
Finn
Flemming M
FM
Poulsen
Birthe B
BB
Kragelund
D002118:Calcium / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051580:Neuronal Calcium-Sensor Proteins / Q000737:chemistry* / Q000378:metabolism; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D013329:Structure-Activity Relationship
D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D002118:Calcium