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Characterization and Evolution of Transmembrane Proteins with Focus on G-protein coupled receptors in Pre-vertebrate Species
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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. , p. 42
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 548
Keywords [en]
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: urn:nbn:se:uu:diva-121696ISBN: 978-91-554-7773-8 (print)OAI: oai:DiVA.org:uu-121696DiVA, id: diva2:306144
Public defence
2010-05-15, B42, BMC, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-23 Created: 2010-03-27 Last updated: 2018-01-12Bibliographically approved
List of papers
1. The amphioxus (Branchiostoma floridae) genome contains a highly diversified set of G protein-coupled receptors
Open this publication in new window or tab >>The amphioxus (Branchiostoma floridae) genome contains a highly diversified set of G protein-coupled receptors
2008 (English)In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 8, p. 9-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: G protein-coupled receptors (GPCRs) are one of the largest families of genes in mammals. Branchiostoma floridae (amphioxus) is one of the species most closely related species to vertebrates. RESULTS: 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). Surprisingly, the Adhesion GPCR repertoire in amphioxus includes receptors with many new domains not previously observed in this family. We found many Rhodopsin GPCRs from all main groups including many amine and peptide binding receptors and several previously uncharacterized expansions were also identified. This genome has however no genes coding for bitter taste receptors (TAS2), the sweet and umami (TAS1), pheromone (VR1 or VR2) or mammalian olfactory receptors. CONCLUSION: The amphioxus genome is remarkably rich in various GPCR subtypes while the main GPCR groups known to sense exogenous substances (such as Taste 2, mammalian olfactory, nematode chemosensory, gustatory, vomeronasal and odorant receptors) in other bilateral species are absent.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-99148 (URN)10.1186/1471-2148-8-9 (DOI)000253541900001 ()18199322 (PubMedID)
Available from: 2009-03-09 Created: 2009-03-09 Last updated: 2017-12-13Bibliographically approved
2. The Secretin GPCRs descended from the family of Adhesion GPCRs
Open this publication in new window or tab >>The Secretin GPCRs descended from the family of Adhesion GPCRs
Show others...
2009 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 26, no 1, p. 71-84Article 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.

Keywords
evolution, GPCR, G-protein, 7TM, EGF, GRAFS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121693 (URN)10.1093/molbev/msn228 (DOI)000261681900008 ()18845549 (PubMedID)
Available from: 2010-03-27 Created: 2010-03-27 Last updated: 2017-12-12Bibliographically approved
3. Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin
Open this publication in new window or tab >>Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin
2009 (English)In: BMC Biology, ISSN 1741-7007, E-ISSN 1741-7007, Vol. 7, p. 50-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Membrane proteins 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. RESULTS: Here we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. 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). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning alpha-helix. Further, we have identified and characterized new gene families and novel members of existing families. CONCLUSION: Here we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121692 (URN)10.1186/1741-7007-7-50 (DOI)000270292300001 ()19678920 (PubMedID)
Available from: 2010-03-27 Created: 2010-03-27 Last updated: 2017-12-12Bibliographically approved
4. Independent HHsearch, Needleman-Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families
Open this publication in new window or tab >>Independent HHsearch, Needleman-Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families
Show others...
2011 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 28, no 9, p. 2471-2480Article in journal (Refereed) Published
Abstract [en]

Several families of G protein-coupled receptors (GPCR) show no significant sequence similarities and it has been debated which groups of GPCRs that share a common origin. We developed and performed integrated independent HHsearch, Needleman-Wunsch-based and motif analyses on almost 7000 unique GPCRs from twelve species. Moreover, we mined the evolutionary important Trichoplax adhaerens, Nematostella vectensis, Thalassiosira pseudonana and Strongylocentrotus purpuratus genomes, revealing remarkably rich vertebrate-like repertoires already in the early Metazoan species. We found strong evidence for that the Adhesion and Frizzled families are children to the cAMP family with HHsearch homology probabilities of 99.8% and 99.4%, respectively, also supported by the Needleman-Wunsch analysis and several motifs. We also found that the large Rhodopsin family is likely a child of the cAMP family with a HHsearch homology probability of 99.4% and conserved motifs. Therefore, we suggest that the Adhesion and Frizzled families originated from the cAMP family in an event close to that which gave rise to the Rhodopsin family. We also found convincing evidence that the Rhodopsin family is parent to the important sensory Taste 2, Vomeronasal type 1 and Nematode chemoreceptor families. The insect odorant, gustatory and Trehalose receptors, frequently referred to as GPCRs, form a separate cluster without relationship to the other families and we speculate, based on these and other’s results, that these families are ligand-gated ion channels rather than GPCRs. Overall, we suggest common descent of at least 97% of the GPCRs sequences found in humans, including all the main families.

Keywords
evolution, GPCR, GPCRs, G-protein, 7TM, Rhodopsin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121694 (URN)10.1093/molbev/msr061 (DOI)000294552700009 ()
Available from: 2010-03-27 Created: 2010-03-27 Last updated: 2017-12-12Bibliographically approved

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