A 2A  Receptor Homodimer-Disrupting Sequence Efficiently Delivered by a Protease-Resistant, Cyclic CPP Vector

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Abstract

G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.

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Most cited references 27

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Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor.

N Kunishima, Y Shimada, Y Tsuji … (2000)

The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Here we have determined three different crystal structures of the extracellular ligand-binding region of mGluR1--in a complex with glutamate and in two unliganded forms. They all showed disulphide-linked homodimers, whose 'active' and 'resting' conformations are modulated through the dimeric interface by a packed alpha-helical structure. The bi-lobed protomer architectures flexibly change their domain arrangements to form an 'open' or 'closed' conformation. The structures imply that glutamate binding stabilizes both the 'active' dimer and the 'closed' protomer in dynamic equilibrium. Movements of the four domains in the dimer are likely to affect the separation of the transmembrane and intracellular regions, and thereby activate the receptor. This scheme in the initial receptor activation could be applied generally to G-protein-coupled neurotransmitter receptors that possess extracellular ligand-binding sites.

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Heterodimerization is required for the formation of a functional GABA(B) receptor.

Lisa J White, Carol A. Barnes, Traci Fraser … (1998)

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABA(B) receptor (GABA(B)R1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABA(B)R2-receptor subtype forms heterodimers with GABA(B)R1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABA(B)R2 in HEK293T cells, GABA(B)R1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABA(B) receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2.

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Structural Insights into Metabotropic Glutamate Receptor Activation

Antoine Koehl, Hongli Hu, Dan Feng … (2019)

Metabotropic glutamate receptors are Family C G protein coupled receptors that form obligate dimers and possess extracellular ligand binding Venus flytrap (VFT) domains, which are linked via cysteine rich domains (CRDs) to their 7-transmembrane (7TM) domain. Spectroscopic studies show that signaling is a dynamic process, with large scale conformational changes underlying the transmission of signal from the extracellular VFTs to the G protein-coupling domains (7TMs) in the membrane. Using a combination of x-ray crystallography, cryo-electron microscopy and signaling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the VFTs leads to a compaction of the intersubunit dimer interface, thereby bringing the CRDs into close proximity. Interactions between the CRDs and the second extracellular loops of the receptor enable the rigid body repositioning of the 7TM domains, which come into contact with each other to initiate signaling.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 05 October 2019

Publication date Collection: October 2019

Volume: 20

Issue: 19

Electronic Location Identifier: 4937

Affiliations

[1 ]Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain; maria.gallo@ 123456upf.edu

[2 ]Department of Biochemistry and Physiology, University of Barcelona, 08028 Barcelona, Spain; dimartts@ 123456hotmail.com

[3 ]Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salut Carlos III, 28029 Madrid, Spain

[4 ]Faculty of Chemistry, University of Barcelona, 08028 Barcelona, Spain

Author notes

[* ]Correspondence: rfranco123@ 123456gmail.com (R.F.); david.andreu@ 123456upf.edu (D.A.); Tel.: +34-934021208 (R.F.); +34-933160868 (D.A.)

[†]

The authors contributed equally to this work.

[‡]

The authors contributed equally to this work.

Author information

Maria Gallo https://orcid.org/0000-0001-9099-7235

Rafael Franco https://orcid.org/0000-0003-2549-4919

Article

Publisher ID: ijms-20-04937

DOI: 10.3390/ijms20194937

PMC ID: 6801510

PubMed ID: 31590403

SO-VID: fbedee90-11a8-420e-8d5b-323d79f95af5

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

A _2A Receptor Homodimer-Disrupting Sequence Efficiently Delivered by a Protease-Resistant, Cyclic CPP Vector

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Abstract

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Most cited references 27

Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor.

Heterodimerization is required for the formation of a functional GABA(B) receptor.

Structural Insights into Metabotropic Glutamate Receptor Activation

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