Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications
Abstract
The understanding of G-protein coupled receptors (GPCRs) is undergoing a revolution due to increased information about their signaling and the experimental determination of structures for more than 25 receptors. The availability of at least one receptor structure for each of the GPCR classes, well separated in sequence space, enables an integrated superfamily-wide analysis to identify signatures involving the role of conserved residues, conserved contacts, and downstream signaling in the context of receptor structures. In this study, we align the transmembrane (TM) domains of all experimental GPCR structures to maximize the conserved inter-helical contacts. The resulting superfamily-wide GpcR Sequence-Structure (GRoSS) alignment of the TM domains for all human GPCR sequences is sufficient to generate a phylogenetic tree that correctly distinguishes all different GPCR classes, suggesting that the class-level differences in the GPCR superfamily are encoded at least partly in the TM domains. The inter-helical contacts conserved across all GPCR classes describe the evolutionarily conserved GPCR structural fold. The corresponding structural alignment of the inactive and active conformations, available for a few GPCRs, identifies activation hot-spot residues in the TM domains that get rewired upon activation. Many GPCR mutations, known to alter receptor signaling and cause disease, are located at these conserved contact and activation hot-spot residue positions. The GRoSS alignment places the chemosensory receptor subfamilies for bitter taste (TAS2R) and pheromones (Vomeronasal, VN1R) in the rhodopsin family, known to contain the chemosensory olfactory receptor subfamily. The GRoSS alignment also enables the quantification of the structural variability in the TM regions of experimental structures, useful for homology modeling and structure prediction of receptors. Furthermore, this alignment identifies structurally and functionally important residues in all human GPCRs. These residues can be used to make testable hypotheses about the structural basis of receptor function and about the molecular basis of disease-associated single nucleotide polymorphisms.
Additional Information
© 2016 Cvicek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: September 10, 2015; Accepted: February 11, 2016; Published: March 30, 2016. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. They are also available in a convenient searchable form at http://www.gpcrs.org. This work was supported by: Gifts to the Materials and Process Simulation Center at Caltech, NIH (R01NS073115 and R01AI040567), Defense University Research Instrumentation Program (DURIP) grant (N00014-12-1-0818), and NSF (EFRI-1332411) to WAG; College of Science & Engineering and the University of Minnesota Supercomputing Institute to VC; and Cedars-Sinai Medical Center (Startup Funds) to RA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank Dr. Soo-Kyung Kim, Mr. Adam Griffith, Ms. Sijia Dong, Dr. Caitlin Scott, and Dr. Andrea Kirkpatrick for helpful discussions. RA would like to thank Dr. Suguna Sakkiah for generating the detailed list of available GPCR structures. Author Contributions: Conceived and designed the experiments: RA VC WAG. Performed the experiments: VC. Analyzed the data: VC WAG RA. Wrote the paper: VC WAG RA.Attached Files
Published - journal.pcbi.1004805.PDF
Supplemental Material - journal.pcbi.1004805.s001.PDF
Supplemental Material - journal.pcbi.1004805.s002.CSV
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Additional details
- PMCID
- PMC4814114
- Eprint ID
- 65890
- Resolver ID
- CaltechAUTHORS:20160404-101449544
- NIH
- R01NS073115
- NIH
- R01AI040567
- Office of Naval Research (ONR)
- N00014-12-1-0818
- NSF
- EFRI-1332411
- University of Minnesota
- Cedars-Sinai Medical Center
- Created
-
2016-04-04Created from EPrint's datestamp field
- Updated
-
2019-10-03Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1161