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Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.

Cvicek V, Goddard WA, Abrol R - PLoS Comput. Biol. (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Materials and Process Simulation Center, California Institute of Technology, Pasadena, California, United States of America.

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.

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Related in: MedlinePlus

Magnitude of the rigid body moves of the helices necessary to map one structure to another.All TMs 1–7 from all available structure pairs were compared and each symbol denotes which TM is the data point from. The coordinate system is defined in the text. The maximal observed deviation is approximately proportional to the sequence dissimilarity of the two compared TMs, and it follows the same trend within class A (blue symbols) and across the GPCR superfamily (green symbols). The red symbols, which correspond to the active-inactive structure pairs, show rigid body moves caused by receptor activation. S10 Fig has an analogous plot of residual RMSD vs. similarity for each helix after the best rigid body transformation. RMSD shows a similar trend as the plots in this figure.
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pcbi.1004805.g009: Magnitude of the rigid body moves of the helices necessary to map one structure to another.All TMs 1–7 from all available structure pairs were compared and each symbol denotes which TM is the data point from. The coordinate system is defined in the text. The maximal observed deviation is approximately proportional to the sequence dissimilarity of the two compared TMs, and it follows the same trend within class A (blue symbols) and across the GPCR superfamily (green symbols). The red symbols, which correspond to the active-inactive structure pairs, show rigid body moves caused by receptor activation. S10 Fig has an analogous plot of residual RMSD vs. similarity for each helix after the best rigid body transformation. RMSD shows a similar trend as the plots in this figure.

Mentions: Fig 9 shows the observed move sizes, when the individual TM helices are treated as rigid bodies. Each pair of known structures was first aligned together, then each helix of the first protein was individually aligned to the corresponding helix of the second protein and the size of the move was measured. The center of mass translation was broken down into the direction along the helical axis and a direction perpendicular to it. The “tilt of axis” measures how much axis 1 had to be rotated to axis 2. And finally the “rotation around axis” measures the necessary rotation around the axis to map the corresponding atoms to each other.


Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.

Cvicek V, Goddard WA, Abrol R - PLoS Comput. Biol. (2016)

Magnitude of the rigid body moves of the helices necessary to map one structure to another.All TMs 1–7 from all available structure pairs were compared and each symbol denotes which TM is the data point from. The coordinate system is defined in the text. The maximal observed deviation is approximately proportional to the sequence dissimilarity of the two compared TMs, and it follows the same trend within class A (blue symbols) and across the GPCR superfamily (green symbols). The red symbols, which correspond to the active-inactive structure pairs, show rigid body moves caused by receptor activation. S10 Fig has an analogous plot of residual RMSD vs. similarity for each helix after the best rigid body transformation. RMSD shows a similar trend as the plots in this figure.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4814114&req=5

pcbi.1004805.g009: Magnitude of the rigid body moves of the helices necessary to map one structure to another.All TMs 1–7 from all available structure pairs were compared and each symbol denotes which TM is the data point from. The coordinate system is defined in the text. The maximal observed deviation is approximately proportional to the sequence dissimilarity of the two compared TMs, and it follows the same trend within class A (blue symbols) and across the GPCR superfamily (green symbols). The red symbols, which correspond to the active-inactive structure pairs, show rigid body moves caused by receptor activation. S10 Fig has an analogous plot of residual RMSD vs. similarity for each helix after the best rigid body transformation. RMSD shows a similar trend as the plots in this figure.
Mentions: Fig 9 shows the observed move sizes, when the individual TM helices are treated as rigid bodies. Each pair of known structures was first aligned together, then each helix of the first protein was individually aligned to the corresponding helix of the second protein and the size of the move was measured. The center of mass translation was broken down into the direction along the helical axis and a direction perpendicular to it. The “tilt of axis” measures how much axis 1 had to be rotated to axis 2. And finally the “rotation around axis” measures the necessary rotation around the axis to map the corresponding atoms to each other.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Materials and Process Simulation Center, California Institute of Technology, Pasadena, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus