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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

Testing the robustness of the alignment of the Vomeronasal receptors with the other groups.The table shows similarity between TMs averaged over all pairs of sequences formed from the two groups (red denotes high similarity, blue low similarity). For most TMs the optimal choices agree with the optimal alignment to Aα (full table in S5 Fig); all combinations are shown only for TM5. The same table but using the GPCRtm substitution matrix [74] instead of BLOSUM62 is shown in S7 Fig. GPCRtm was developed in particular for GPCR proteins, but in this case both matrices result in the same alignment.
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pcbi.1004805.g003: Testing the robustness of the alignment of the Vomeronasal receptors with the other groups.The table shows similarity between TMs averaged over all pairs of sequences formed from the two groups (red denotes high similarity, blue low similarity). For most TMs the optimal choices agree with the optimal alignment to Aα (full table in S5 Fig); all combinations are shown only for TM5. The same table but using the GPCRtm substitution matrix [74] instead of BLOSUM62 is shown in S7 Fig. GPCRtm was developed in particular for GPCR proteins, but in this case both matrices result in the same alignment.

Mentions: The profile of the vomeronasal group aligns better with class Aα compared to classes B and C, but there is still a gap of length 2 near the center of TM5. We remove the gap in such a way that the residue, which aligns with 5.50 stays fixed. To check that this is indeed the best alignment we explore small changes in the alignment by shifting individual TM by up to ±5 residues. In Fig 3 we see that for TMs 1 to 4, our current alignment gives the highest sequence similarity with Aα, so the alignment of these TMs is correct. However, for TM5, the alignment shifted by -1 or +2 residues gives higher similarity with Aα. Nevertheless, the similarity with groups Aβ, Aγ, Aδ, and B is the highest for our current alignment. We therefore keep the current choice.


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)

Testing the robustness of the alignment of the Vomeronasal receptors with the other groups.The table shows similarity between TMs averaged over all pairs of sequences formed from the two groups (red denotes high similarity, blue low similarity). For most TMs the optimal choices agree with the optimal alignment to Aα (full table in S5 Fig); all combinations are shown only for TM5. The same table but using the GPCRtm substitution matrix [74] instead of BLOSUM62 is shown in S7 Fig. GPCRtm was developed in particular for GPCR proteins, but in this case both matrices result in the same alignment.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004805.g003: Testing the robustness of the alignment of the Vomeronasal receptors with the other groups.The table shows similarity between TMs averaged over all pairs of sequences formed from the two groups (red denotes high similarity, blue low similarity). For most TMs the optimal choices agree with the optimal alignment to Aα (full table in S5 Fig); all combinations are shown only for TM5. The same table but using the GPCRtm substitution matrix [74] instead of BLOSUM62 is shown in S7 Fig. GPCRtm was developed in particular for GPCR proteins, but in this case both matrices result in the same alignment.
Mentions: The profile of the vomeronasal group aligns better with class Aα compared to classes B and C, but there is still a gap of length 2 near the center of TM5. We remove the gap in such a way that the residue, which aligns with 5.50 stays fixed. To check that this is indeed the best alignment we explore small changes in the alignment by shifting individual TM by up to ±5 residues. In Fig 3 we see that for TMs 1 to 4, our current alignment gives the highest sequence similarity with Aα, so the alignment of these TMs is correct. However, for TM5, the alignment shifted by -1 or +2 residues gives higher similarity with Aα. Nevertheless, the similarity with groups Aβ, Aγ, Aδ, and B is the highest for our current alignment. We therefore keep the current choice.

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