The C-terminal tail of human neuronal calcium sensor 1 regulates the conformational stability of the Ca²⁺₋ activated state.
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The C-terminal tail of human neuronal calcium sensor 1 regulates the conformational stability of the Ca²⁺₋ activated state. / Heidarsson, Pétur O; Bjerrum-Bohr, Ida J; Jensen, Gitte A; Pongs, Olaf; Finn, Bryan E; Poulsen, Flemming M; Kragelund, Birthe B.
In: J MOL BIOL, Vol. 417, No. 1-2, 1-2, 2012, p. 51-64.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The C-terminal tail of human neuronal calcium sensor 1 regulates the conformational stability of the Ca²⁺₋ activated state.
AU - Heidarsson, Pétur O
AU - Bjerrum-Bohr, Ida J
AU - Jensen, Gitte A
AU - Pongs, Olaf
AU - Finn, Bryan E
AU - Poulsen, Flemming M
AU - Kragelund, Birthe B
PY - 2012
Y1 - 2012
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 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.
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 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.
KW - Humans
KW - Protein Conformation
KW - Protein Binding
KW - Magnetic Resonance Spectroscopy
KW - Calcium/metabolism
KW - Structure-Activity Relationship
KW - Neuronal Calcium-Sensor Proteins/chemistry/metabolism
KW - Neuropeptides/chemistry/metabolism
KW - Protein Stability
KW - Humans
KW - Protein Conformation
KW - Protein Binding
KW - Magnetic Resonance Spectroscopy
KW - Calcium/metabolism
KW - Structure-Activity Relationship
KW - Neuronal Calcium-Sensor Proteins/chemistry/metabolism
KW - Neuropeptides/chemistry/metabolism
KW - Protein Stability
M3 - SCORING: Journal article
VL - 417
SP - 51
EP - 64
JO - J MOL BIOL
JF - J MOL BIOL
SN - 0022-2836
IS - 1-2
M1 - 1-2
ER -
