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 P.; Burgoyne, Robert D.; Mayans, Olga; Derrick, Jeremy P.; Lian, Lu-Yun

Neuronal Calcium Sensor-1 Binds the D2 Dopamine Receptor and G-protein-coupled Receptor Kinase 1 (GRK1) Peptides Using Different Modes of Interactions

Dateien

Pandalaneni_0-349905.pdfGröße: 3.01 MBDownloads: 261

Datum

2015

Autor:innen

Pandalaneni, Sravan

Karuppiah, Vijaykumar

Saleem, Muhammad

Haynes, Lee P.

Burgoyne, Robert D.

Mayans, Olga

Derrick, Jeremy P.

Lian, Lu-Yun

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Journal of Biological Chemistry. 2015, 290(30), pp. 18744-18756. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.M114.627059

Zusammenfassung

Neuronal calcium sensor-1 (NCS-1) is the primordial member of the neuronal calcium sensor family of EF-hand Ca(2+)-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 Ca(2+)/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 Ca(2+)/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 Ca(2+)/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.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

PANDALANENI, Sravan, Vijaykumar KARUPPIAH, Muhammad SALEEM, Lee P. HAYNES, Robert D. BURGOYNE, Olga MAYANS, Jeremy P. DERRICK, Lu-Yun LIAN, 2015. Neuronal Calcium Sensor-1 Binds the D2 Dopamine Receptor and G-protein-coupled Receptor Kinase 1 (GRK1) Peptides Using Different Modes of Interactions. In: Journal of Biological Chemistry. 2015, 290(30), pp. 18744-18756. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.M114.627059

BibTex

@article{Pandalaneni2015-07-24Neuro-34939,
  year={2015},
  doi={10.1074/jbc.M114.627059},
  title={Neuronal Calcium Sensor-1 Binds the D2 Dopamine Receptor and G-protein-coupled Receptor Kinase 1 (GRK1) Peptides Using Different Modes of Interactions},
  number={30},
  volume={290},
  issn={0021-9258},
  journal={Journal of Biological Chemistry},
  pages={18744--18756},
  author={Pandalaneni, Sravan and Karuppiah, Vijaykumar and Saleem, Muhammad and Haynes, Lee P. and Burgoyne, Robert D. and Mayans, Olga and Derrick, Jeremy P. and Lian, Lu-Yun}
}

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