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The Secretin GPCRs descended from the family of Adhesion GPCRs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2009 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 26, no 1, 71-84 p.Article in journal (Refereed) Published
Abstract [en]

The Adhesion G-protein-coupled receptors (GPCRs) are the most complex gene family among GPCRs with large genomic size, multiple introns, and a fascinating flora of functional domains, though the evolutionary origin of this family has been obscure. Here we studied the evolution of all class B (7tm2)-related genes, including the Adhesion, Secretin, and Methuselah families of GPCRs with a focus on nine genomes. We found that the cnidarian genome of Nematostella vectensis has a remarkably rich set of Adhesion GPCRs with a broad repertoire of N-terminal domains although this genome did not have any Secretin GPCRs. Moreover, the single-celled and colony-forming eukaryotes Monosiga brevicollis and Dictyostelium discoideum contain Adhesion-like GPCRs although these genomes do not have any Secretin GPCRs suggesting that the Adhesion types of GPCRs are the most ancient among class B GPCRs. Phylogenetic analysis found Adhesion group V (that contains GPR133 and GPR144) to be the closest relative to the Secretin family in the Adhesion family. Moreover, Adhesion group V sequences in N. vectensis share the same splice site setup as the Secretin GPCRs. Additionally, one of the most conserved motifs in the entire Secretin family is only found in group V of the Adhesion family. We suggest therefore that the Secretin family of GPCRs could have descended from group V Adhesion GPCRs. We found a set of unique Adhesion-like GPCRs in N. vectensis that have long N-termini containing one Somatomedin B domain each, which is a domain configuration similar to that of a set of Adhesion-like GPCRs found in Branchiostoma floridae. These sequences show slight similarities to Methuselah sequences found in insects. The extended class B GPCRs have a very complex evolutionary history with several species-specific expansions, and we identified at least 31 unique N-terminal domains originating from other protein classes. The overall N-terminal domain structure, however, concurs with the phylogenetic analysis of the transmembrane domains, thus enabling us to track the origin of most of the subgroups.

Place, publisher, year, edition, pages
2009. Vol. 26, no 1, 71-84 p.
Keyword [en]
evolution, GPCR, G-protein, 7TM, EGF, GRAFS
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-121693DOI: 10.1093/molbev/msn228ISI: 000261681900008PubMedID: 18845549OAI: oai:DiVA.org:uu-121693DiVA: diva2:306142
Available from: 2010-03-27 Created: 2010-03-27 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Characterization and Evolution of Transmembrane Proteins with Focus on G-protein coupled receptors in Pre-vertebrate Species
Open this publication in new window or tab >>Characterization and Evolution of Transmembrane Proteins with Focus on G-protein coupled receptors in Pre-vertebrate Species
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

G protein-coupled receptors (GPCRs) are one of the largest protein families in mammals. GPCRs are instrumental for hormonal and neurotransmitter signalling and are important in all major physiological systems of the body. Paper I describes the repertoire of GPCRs in Branchiostoma floridae, which is one of the species most closely related species to vertebrates. Mining and phylogenetic analysis of the amphioxus genome showed the presence of at least 664 distinct GPCRs distributed among all the main families of GPCRs; Glutamate (18), Rhodopsin (570), Adhesion (37), Frizzled (6) and Secretin (16). Paper II contains studies of the Adhesion, Methuselah and Secretin GPCR families in nine genomes. The Adhesion GPCRs are the most complex gene family among GPCRs with large genomic size, multiple introns and a fascinating flora of functional domains. Phylogenetic analysis showed Adhesion group V (that contains GPR133 and GPR144) to be the closest relative to the Secretin family among the groups in the Adhesion family, which was also supported by splice site setup and conserved motifs. Paper III examines the repertoire of human transmembrane proteins. These form key nodes in mediating the cell’s interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups; Receptors (63 groups, 1,352 members), Transporters (89 groups, 817 members) or Enzymes (7 groups, 533 members). In addition, 74 Miscellaneous groups were shown to include 697 members. Paper IV clarifies the hierarchy of the main families and evolutionary origin of majority of the metazoan GPCR families. Overall, it suggests common decent of at least 97% of the GPCRs sequences found in humans, including all the main families.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 42 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 548
Keyword
G protein-coupled receptors, GPCR, Membrane protein, Rhodopsin, Adhesion, Secretin, Evolution, Bioinformatics, Phylogeny
National Category
Pharmacology and Toxicology Bioinformatics and Systems Biology
Research subject
Bioinformatics; Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-121696 (URN)978-91-554-7773-8 (ISBN)
Public defence
2010-05-15, B42, BMC, Uppsala, 09:00 (English)
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Available from: 2010-04-23 Created: 2010-03-27 Last updated: 2010-04-23Bibliographically approved

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Lagerström, Malin CFredriksson, RobertSchiöth, Helgi B

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