TY - JOUR
T1 - The C-terminal tail of human neuronal calcium sensor 1 regulates the conformational stability of the Ca2+-activated state
AU - Heiðarsson, Pétur Orri
AU - Bjerrum-Bohr, Ida Jannike
AU - Jensen, Gitte A.
AU - Pongs, Olaf
AU - Finn, Bryan E.
AU - Poulsen, Flemming Martin
AU - Kragelund, Birthe Brandt
PY - 2012/3/16
Y1 - 2012/3/16
N2 - 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.
AB - 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.
U2 - 10.1016/j.jmb.2011.12.049
DO - 10.1016/j.jmb.2011.12.049
M3 - Journal article
C2 - 22227393
SN - 0022-2836
VL - 417
SP - 51
EP - 64
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1-2
ER -