Selectivity determinants of GPCR-G-protein binding

Tilman Flock; Alexander S Hauser; Nadia Lund; David E Gloriam; Santhanam Balaji; M Madan Babu

doi:10.1038/nature22070

Selectivity determinants of GPCR-G-protein binding

Tilman Flock, Alexander S Hauser, Nadia Lund, David E Gloriam, Santhanam Balaji, M Madan Babu

153 Citationer (Scopus)

Abstract

The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	545
Udgave nummer	7654
Sider (fra-til)	317-322
Antal sider	6
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature22070
Status	Udgivet - 18 maj 2017

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10.1038/nature22070

http://europepmc.org/articles/pmc5846738?pdf=renderLicens: Andet

Citationsformater

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AU - Flock, Tilman

AU - Hauser, Alexander S

AU - Lund, Nadia

AU - Gloriam, David E

AU - Balaji, Santhanam

AU - Babu, M Madan

PY - 2017/5/18

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N2 - The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

AB - The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

KW - Amino Acid Sequence

KW - GPCR

KW - Evolution, Molecular

KW - G-protein-coupled receptor

KW - G proteins

KW - Structural Homology, Protein

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Selectivity determinants of GPCR-G-protein binding

Abstract

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