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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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TM 3 sequence alignment for the 25 crystal structures.Other TMs are shown in Fig 6. The sequences are taken from the selected PDB files. The TM helix residues are colored in the Zappos scheme, which captures the chemical nature of each residue (e.g. helix breakers, proline and glycine, are shown in purple). The loop residues are shown in grey. The BW n.50 residue (numbering displayed below the sequences) is the most conserved within the class A. The consensus sequence is most similar to class A, because most sequences are from this class. The largest differences are for the last 5 sequences, which belong to the classes B, C, and F. The figure was prepared using Jalview.
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pcbi.1004805.g005: TM 3 sequence alignment for the 25 crystal structures.Other TMs are shown in Fig 6. The sequences are taken from the selected PDB files. The TM helix residues are colored in the Zappos scheme, which captures the chemical nature of each residue (e.g. helix breakers, proline and glycine, are shown in purple). The loop residues are shown in grey. The BW n.50 residue (numbering displayed below the sequences) is the most conserved within the class A. The consensus sequence is most similar to class A, because most sequences are from this class. The largest differences are for the last 5 sequences, which belong to the classes B, C, and F. The figure was prepared using Jalview.

Mentions: Fig 5 shows the alignment of the TM3 regions for all the known crystal structures (other TMs are shown in Fig 6). We see that the DRY motif at positions 3.49–3.51 is highly conserved within the 20 class A sequences, and even when there are mutations only similar amino acids occur: ERY, DRF (however, there exist class A GPCRs without this motif, e.g. PTGDR has ECW [83]). In classes B, C, and F the DRY motif is not conserved at all.


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)

TM 3 sequence alignment for the 25 crystal structures.Other TMs are shown in Fig 6. The sequences are taken from the selected PDB files. The TM helix residues are colored in the Zappos scheme, which captures the chemical nature of each residue (e.g. helix breakers, proline and glycine, are shown in purple). The loop residues are shown in grey. The BW n.50 residue (numbering displayed below the sequences) is the most conserved within the class A. The consensus sequence is most similar to class A, because most sequences are from this class. The largest differences are for the last 5 sequences, which belong to the classes B, C, and F. The figure was prepared using Jalview.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004805.g005: TM 3 sequence alignment for the 25 crystal structures.Other TMs are shown in Fig 6. The sequences are taken from the selected PDB files. The TM helix residues are colored in the Zappos scheme, which captures the chemical nature of each residue (e.g. helix breakers, proline and glycine, are shown in purple). The loop residues are shown in grey. The BW n.50 residue (numbering displayed below the sequences) is the most conserved within the class A. The consensus sequence is most similar to class A, because most sequences are from this class. The largest differences are for the last 5 sequences, which belong to the classes B, C, and F. The figure was prepared using Jalview.
Mentions: Fig 5 shows the alignment of the TM3 regions for all the known crystal structures (other TMs are shown in Fig 6). We see that the DRY motif at positions 3.49–3.51 is highly conserved within the 20 class A sequences, and even when there are mutations only similar amino acids occur: ERY, DRF (however, there exist class A GPCRs without this motif, e.g. PTGDR has ECW [83]). In classes B, C, and F the DRY motif is not conserved at all.

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