Neuronal Calcium Sensor-1 binds the D2 dopamine receptor and G-protein-coupled receptor kinase 1 (GRK1) peptides using different modes of interactions


Pandalaneni, Sravan, Karuppiah, Vijaykumar, Saleem, Muhammad, Haynes, Lee ORCID: 0000-0002-1296-0338, Burgoyne, Bob ORCID: 0000-0002-9219-0387, Mayans, Olga, Derrick, Jeremy P and Lian, Lu-Yun (2015) Neuronal Calcium Sensor-1 binds the D2 dopamine receptor and G-protein-coupled receptor kinase 1 (GRK1) peptides using different modes of interactions. The Journal of Biological Chemistry, 290 (30). pp. 18744-18756.

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Abstract

Neuronal calcium sensor-1 (NCS-1) is the primordial member of the neuronal calcium sensor family of EF-hand Ca2+-binding proteins. It interacts with both the G-protein-coupled receptor (GPCR) dopamine D2 receptor (D2R), regulating its internalization 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 binds. The different binding modes are made possible by the C-lobe-binding site of NCS-1, which adopts alternative conformations in each complex. C-terminal residues Ser-178–Val-190 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 α-helix. Removal of Ser-178–Val-190 generated a C-terminal truncation mutant that 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 ramifications for the target specificity and diversity of NCS-1.

Item Type: Article
Uncontrolled Keywords: calcium, dopamine, G protein-coupled receptor (GPCR), receptor internalization, x-ray crystallography, D2 dopamine receptor, GRK1, neuronal calcium sensor-1
Depositing User: Symplectic Admin
Date Deposited: 28 Apr 2016 10:19
Last Modified: 25 Jan 2023 04:26
DOI: 10.1074/jbc.M114.627059
Open Access URL: http://www.jbc.org/content/290/30/18744.long
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3000894
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