From cradle to twilight: The carboxyl terminus directs the fate of the A2A-adenosine receptor

Keuerleber, Simon; Gsandtner, Ingrid; Freissmuth, Michael

doi:10.1016/j.bbamem.2010.05.009

Cited by 34 publications

(36 citation statements)

References 86 publications

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“…Although experimental data related to the function of A2A-ct is very limited, it has been proposed to take part in different protein-protein interactions, including interactions with dopamine D2 receptor, ARNO/cytohesin-2, b-arrestins, and CaM (43,73,74). Our SRCD, SAXS, and NMR results support the previously predicted disordered and extended conformation of the A2A-ct in solution.…”

Section: Discussionsupporting

confidence: 91%

Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Piirainen

Hellman

Tossavainen

et al. 2015

Biophysical Journal

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Understanding how ligands bind to G-protein-coupled receptors and how binding changes receptor structure to affect signaling is critical for developing a complete picture of the signal transduction process. The adenosine A2A receptor (A2AR) is a particularly interesting example, as it has an exceptionally long intracellular carboxyl terminus, which is predicted to be mainly disordered. Experimental data on the structure of the A2AR C-terminus is lacking, because published structures of A2AR do not include the C-terminus. Calmodulin has been reported to bind to the A2AR C-terminus, with a possible binding site on helix 8, next to the membrane. The biological meaning of the interaction as well as its calcium dependence, thermodynamic parameters, and organization of the proteins in the complex are unclear. Here, we characterized the structure of the A2AR C-terminus and the A2AR C-terminus-calmodulin complex using different biophysical methods, including native gel and analytical gel filtration, isothermal titration calorimetry, NMR spectroscopy, and small-angle X-ray scattering. We found that the C-terminus is disordered and flexible, and it binds with high affinity (Kd = 98 nM) to calmodulin without major conformational changes in the domain. Calmodulin binds to helix 8 of the A2AR in a calcium-dependent manner that can displace binding of A2AR to lipid vesicles. We also predicted and classified putative calmodulin-binding sites in a larger group of G-protein-coupled receptors.

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Section: Discussionsupporting

confidence: 91%

Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Piirainen

Hellman

Tossavainen

et al. 2015

Biophysical Journal

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“…1). The model is adapted from that put forth to explain trafficking of the A 2A -receptor through the early secretory pathway [47] and is based on the following – albeit circumstantial – evidence:Oligomer formation is required for ER export of SLC6 transporters. Oligomerization-deficient mutants are retained in the ER [48,49].…”

Section: Introductionmentioning

confidence: 99%

Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

Chiba

Freissmuth

Stockner

2014

Pharmacological Research

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“…the other adenosine receptors) and to the entire class of class A/rhodopsin-like GPCRs 3 (7). Its C terminus is very long (122 amino acids) and, thus, provides docking sites for interacting proteins (8). It lacks the canonical palmitoylated cysteine residue, which is thought to anchor helix 8 in the membrane (9).…”

Section: Introductionmentioning

confidence: 99%

A Two-state Model for the Diffusion of the A2A Adenosine Receptor in Hippocampal Neurons

Thurner

Gsandtner

Kudlacek

et al. 2014

Journal of Biological Chemistry

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Background: Agonist activation slows diffusion of the A2A receptor in the lipid bilayer.Results: In hippocampal neurons, the agonist-induced decrease in mobility was accounted for by both the hydrophobic receptor core and its extended C terminus, which recruited SAP102.Conclusion: The observations are consistent with two diffusion states of the A2A receptor in neurons.Significance: SAP102 regulates access of the A2A receptor to a compartment with restricted mobility.

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From cradle to twilight: The carboxyl terminus directs the fate of the A2A-adenosine receptor

Cited by 34 publications

References 86 publications

Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Human Adenosine A2A Receptor Binds Calmodulin with High Affinity in a Calcium-Dependent Manner

Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

A Two-state Model for the Diffusion of the A2A Adenosine Receptor in Hippocampal Neurons

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