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Crystal structure of C-terminally truncated Neuronal Calcium Sensor (NCS-1) from Rattus norvegicus
Structural highlights
FunctionNCS1_RAT Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner. Directly regulates GRK1 (RHOK), but not GRK2 to GRK5. Can substitute for calmodulin. Stimulates PI4KB kinase activity. Involved in long-term synaptic plasticity through its interaction with PICK1. May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel.[1] Publication Abstract from PubMedNeuronal Calcium Sensor-1 (NCS-1) is the primordial member of the Neuronal Calcium Sensor (NCS) family of EF-hand Ca2+-binding proteins. It interacts with both the G-protein coupled receptor (GPCR) dopamine D2 receptor (D2R), regulating its internalisation and surface expression, and the cognate kinases, GRK1 and GRK2. Determination of the crystal structures of Ca2+/NCS-1 alone and in complex with peptides derived from D2R and GRK1 reveals that the differential recognition is facilitated by the conformational flexibility of the C-lobe binding site. We find that two copies of the D2R peptide bind within the hydrophobic crevice on Ca2+/NCS-1, but only one copy of the GRK1 peptide. The different binding modes are made possible by the C-lobe binding site of NCS-1, which adopts alternate conformations in each complex. C-terminal residues S178-V190 act in concert with the flexible EF3/EF4 loop region to effectively form different peptide binding sites. In the Ca2+/NCS-1-D2R peptide complex, the C-terminal region adopts a 310 helix-turn-310 helix, whereas in the GRK1 peptide complex it forms an alpha-helix. Removal of S178-V190 generated a C-terminal truncation mutant which formed a dimer, indicating that the NCS-1 C-terminal region prevents NCS-1 oligomerization. We propose that the flexible nature of the C-terminal region is essential to allow it to modulate its protein binding sites and adapt its conformation to accommodate both ligands. This appears to be driven by the variability of the conformation of the C-lobe binding site, which has ramification for the target specificity and diversity of NCS-1. Neuronal Calcium Sensor-1 binds the D2 dopamine receptor and G-protein coupled receptor kinase 1 (GRK1) peptides using different modes of interactions.,Pandalaneni S, Karuppiah V, Saleem M, Haynes LP, Burgoyne RD, Mayans O, Derrick JP, Lian LY J Biol Chem. 2015 May 15. pii: jbc.M114.627059. PMID:25979333[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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