Structural Determinants of Calmodulin Binding to the Intracellular C-terminal Domain of the Metabotropic Glutamate Receptor 7A

Department of Neurochemistry, Max Planck Institute for Brain Research, 60528 Frankfurt, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2008; 283(9):5577-88. DOI: 10.1074/jbc.M709505200
Source: PubMed


Calmodulin (CaM) binds in a Ca2+-dependent manner to the intracellular C-terminal domains of most group III metabotropic glutamate receptors (mGluRs). Here
we combined mutational and biophysical approaches to define the structural basis of CaM binding to mGluR 7A. Ca2+/CaM was found to interact with mGluR 7A primarily via its C-lobe at a 1:1 CaM:C-tail stoichiometry. Pulldown experiments
with mutant CaM and mGluR 7A C-tail constructs and high resolution NMR with peptides corresponding to the CaM binding region
of mGluR 7A allowed us to define hydrophobic and ionic interactions required for Ca2+/CaM binding and identified a 1-8-14 CaM-binding motif. The Ca2+/CaM·mGluR 7A peptide complex displays a classical wraparound structure that closely resembles that formed by Ca2+/CaM upon binding to smooth muscle myosin light chain kinase. Our data provide insight into how Ca2+/CaM regulates group III mGluR signaling via competition with intracellular proteins for receptor-binding sites.

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Available from: Rudolf Schemm, Jan 13, 2016
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    • "Structural studies indicate that Ca 2+ /CaM binding to mGlu7a includes interactions with both Ser 862 , a target site for phosphorylation by protein kinase C (Nakajima et al., 1999; Dev et al., 2000; Airas et al., 2001), and the G bg recognition motif (El Far et al., 2001). Recent structural studies have also identified the region from amino acids 856–879 of mGlu7 C-tail to be responsible for CaM binding (Scheschonka et al., 2008). Moreover, the C-tail of mGlu7a displays a PDZ-binding motif (LVI) that has been shown to interact with PICK1 (protein interacting with C kinase 1) (El Far et al., 2000), and this interaction is involved in synaptic transmission and plasticity (Perroy et al., 2002). "
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    • "proteins. This hypothesis is supported by experimental data: The mGluR7a-CT forms an amphipathic a-helix in contact with Calmodulin , while 5 amino acids of the mGluR7b-CT adopt an extended b-sheet conformation in complex with PP1 [5] [11]. "
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