| 1. |
- Hamann, Joerg, et al.
(författare)
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International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors
- 2015
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Ingår i: Pharmacological Reviews. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0031-6997 .- 1521-0081. ; 67:2, s. 338-367
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Forskningsöversikt (refereegranskat)abstract
- The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.
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| 2. |
- Attwood, Misty M., et al.
(författare)
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Highly diversified expansions shaped the evolution of membrane bound proteins in metazoans
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The dramatic increase in membrane proteome complexity is arguably one of the most pivotal evolutionary events that underpins the origin of multicellular animals. However, the origin of a significant number of membrane families involved in metazoan development has not been clarified. In this study, we have manually curated the membrane proteomes of 22 metazoan and 2 unicellular holozoan species. We identify 123,014 membrane proteins in these 24 eukaryotic species and classify 86% of the dataset. We determine 604 functional clusters that are present from the last holozoan common ancestor (LHCA) through many metazoan species. Intriguingly, we show that more than 70% of the metazoan membrane protein families have a premetazoan origin. The data show that enzymes are more highly represented in the LHCA and expand less than threefold throughout metazoan species; in contrast to receptors that are relatively few in the LHCA but expand nearly eight fold within metazoans. Expansions related to cell adhesion, communication, immune defence, and developmental processes are shown in conjunction with emerging biological systems, such as neuronal development, cytoskeleton organization, and the adaptive immune response. This study defines the possible LHCA membrane proteome and describes the fundamental functional clusters that underlie metazoan diversity and innovation.
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| 3. |
- Attwood, Misty M., et al.
(författare)
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Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome
- 2016
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Membrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the a-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.Results: We classified 373 proteins, which represents similar to 7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.Conclusions: We provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.
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| 4. |
- Eriksson, Anders, et al.
(författare)
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Implication of coronin 7 in body weight regulation in humans, mice and flies
- 2015
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. Results: We performed genome wide DNA methylation profiling comparing normal-weight and obese 9-13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. Conclusion: We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.
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| 5. |
- Harty, Breanne L., et al.
(författare)
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Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. Results: Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. Conclusions: Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets.
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| 6. |
- Krishnan, Arunkumar, et al.
(författare)
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Classification, nomenclature, and structural aspects of adhesion GPCRs
- 2016
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Ingår i: Adhesion G Protein-coupled Receptors. - Cham : Springer Publishing Company. - 9783319415215 - 9783319415239 ; , s. 15-41
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Bokkapitel (refereegranskat)abstract
- The adhesion family of G protein-coupled receptors (aGPCRs) is unique among all GPCR families with long N-termini and multiple domains that are implicated in cell-cell and cell-matrix interactions. Initially, aGPCRs in the human genome were phylogenetically classified into nine distinct subfamilies based on their 7TM sequence similarity. This phylogenetic grouping of genes into subfamilies was found to be in congruence in closely related mammals and other vertebrates as well. Over the years, aGPCR repertoires have been mapped in many species including model organisms, and, currently, there is a growing interest in exploring the pharmacological aspects of aGPCRs. Nonetheless, the aGPCR nomenclature has been highly diverse because experts in the field have used different names for different family members based on their characteristics (e.g., epidermal growth factor-seven-span transmembrane (EGF-TM7)), but without harmonization with regard to nomenclature efforts. In order to facilitate naming of orthologs and other genetic variants in different species in the future, the Adhesion-GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposed a unified nomenclature for aGPCRs. Here, we review the classification and the most recent/current nomenclature of aGPCRs and as well discuss the structural topology of the extracellular domain (ECD)/N-terminal fragment (NTF) that is comparable with this 7TM subfamily classification. Of note, we systematically describe the structural domains in the ECD of aGPCR subfamilies and highlight their role in aGPCR-protein interactions.
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| 7. |
- Krishnan, Arunkumar, et al.
(författare)
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Evolutionary hierarchy of vertebrate-like heterotrimeric G protein families
- 2015
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Ingår i: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1055-7903 .- 1095-9513. ; 91, s. 27-40
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Tidskriftsartikel (refereegranskat)abstract
- Heterotrimeric G proteins perform a crucial role as molecular switches controlling various cellular responses mediated by G protein-coupled receptor (GPCR) signaling pathway. Recent data have shown that the vertebrate-like G protein families are found across metazoans and their closest unicellular relatives. However, an overall evolutionary hierarchy of vertebrate-like G proteins, including gene family annotations and in particular mapping individual gene gain/loss events across diverse holozoan lineages is still incomplete. Here, with more expanded invertebrate taxon sampling, we have reconstructed phylogenetic trees for each of the G protein classes/families and provide a robust classification and hierarchy of vertebrate-like heterotrimeric G proteins. Our results further extend the evidence that the common ancestor (CA) of holozoans had at least five ancestral Gα genes corresponding to all major vertebrate Gα classes and contain a total of eight genes including two Gβ and one Gγ. Our results also indicate that the GNAI/O-like gene likely duplicated in the last CA of metazoans to give rise to GNAI- and GNAO-like genes, which are conserved across invertebrates. Moreover, homologs of GNB1-4 paralogon- and GNB5 family-like genes are found in most metazoans and that the unicellular holozoans encode two ancestral Gβ genes. Similarly, most bilaterian invertebrates encode two Gγ genes which include a representative of the GNG gene cluster and a putative homolog of GNG13. Interestingly, our results also revealed key evolutionary events such as the Drosophila melanogaster eye specific Gβ subunit that is found conserved in most arthropods and several previously unidentified species specific expansions within Gαi/o, Gαs, Gαq, Gα12/13 classes and the GNB1-4 paralogon. Also, we provide an overall proposed evolutionary scenario on the expansions of all G protein families in vertebrate tetraploidizations. Our robust classification/hierarchy is essential to further understand the differential roles of GPCR/G protein mediated intracellular signaling system across various metazoan lineages.
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| 8. |
- Krishnan, Arunkumar, et al.
(författare)
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Insights into the Origin of Nematode Chemosensory GPCRs : Putative Orthologs of the Srw Family Are Found across Several Phyla of Protostomes
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3, s. e93048-
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Tidskriftsartikel (refereegranskat)abstract
- Nematode chemosensory GPCRs in Caenorhabditis elegans (NemChRs) are classified into 19 gene families, and are initially thought to have split from the ancestral Rhodopsin family of GPCRs. However, earlier studies have shown that among all 19 NemChR gene families, only the srw family has a clear sequence relationship to the ancestral Rhodopsin GPCR family. Yet, the phylogenetic relationships between the srw family of NemChRs and the Rhodopsin subfamilies are not fully understood. Also, a widespread search was not previously performed to check for the presence of putative srw family-like sequences or the other 18 NemChR families in several new protostome species outside the nematode lineage. In this study, we have investigated for the presence of 19 NemChR families across 26 eukaryotic species, covering basal eukaryotic branches and provide the first evidence that the srw family of NemChRs is indeed present across several phyla of protostomes. We could identify 29 putative orthologs of the srw family in insects (15 genes), molluscs (11 genes) and Schistosoma mansoni (3 genes). Furthermore, using HMM-HMM profile based comparisons and phylogenetic analysis we show that among all Rhodopsin subfamilies, the peptide and SOG (somatostatin/opioid/galanin) subfamilies are phylogenetically the closest relatives to the srw family of NemChRs. Taken together, we demonstrate that the srw family split from the large Rhodopsin family, possibly from the peptide and/or SOG subfamilies, well before the split of the nematode lineage, somewhere close to the divergence of the common ancestor of protostomes. Our analysis also suggests that the srsx family of NemChRs shares a clear sequence homology with the Rhodopsin subfamilies, as well as with few of the vertebrate olfactory receptors. Overall, this study provides further insights into the evolutionary events that shaped the GPCR chemosensory system in protostome species.
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| 9. |
- Krishnan, Arunkumar, et al.
(författare)
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Remarkable similarities between the hemichordate (Saccoglossus kowalevskii) and vertebrate GPCR repertoire
- 2013
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 526:2, s. 122-133
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Tidskriftsartikel (refereegranskat)abstract
- Saccoglossus kowalevskii (the acorn worm) is a hemichordate belonging to the superphylum of deuterostome bilateral animals. Hemichordates are sister group to echinoderms, and closely related to chordates. S. kowalevskii has chordate like morphological traits and serves as an important model organism, helping developmental biologists to understand the evolution of the central nervous system (CNS). Despite being such an important model organism, the signalling system repertoire of the largest family of integral transmembrane receptor proteins, G protein-coupled receptors (GPCRs) is largely unknown in S. kowalevskii. Here, we identified 260 unique GPCRs and classified as many as 257 of them into five main mammalian GPCR families; Glutamate (23), Rhodopsin (212), Adhesion (18), Frizzled (3) and Secretin (1). Despite having a diffuse nervous system, the acorn worm contains well conserved orthologues for human Adhesion and Glutamate family members, with a similar N-terminal domain architecture. This is particularly true for genes involved in CNS development and regulation in vertebrates. The average sequence identity between the GPCR orthologues in human and S. kowalevskii is around 47%, and this is same as observed in couple of the closest vertebrate relatives, Ciona intestinalis (41%) and Branchiostoma floridae (similar to 47%). The Rhodopsin family has fewer members than vertebrates and lacks clear homologues for 6 of the 13 subgroups, including olfactory, chemokine, prostaglandin, purine, melanocyte concentrating hormone receptors and MAS-related receptors. However, the peptide and somatostatin binding receptors have expanded locally in the acorn worm. Overall, this study is the first large scale analysis of a major signalling gene superfamily in the hemichordate lineage. The establishment of orthologue relationships with genes involved in neurotransmission and development of the CNS in vertebrates provides a foundation for understanding the evolution of signal transduction and allows for further investigation of the hemichordate neurobiology.
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| 10. |
- Krishnan, Arunkumar, et al.
(författare)
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The GPCR repertoire in the demosponge Amphimedon queenslandica : insights into the GPCR system at the early divergence of animals
- 2014
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: G protein-coupled receptors (GPCRs) play a central role in eukaryotic signal transduction. However, the GPCR component of this signalling system, at the early origins of metazoans is not fully understood. Here we aim to identify and classify GPCRs in Amphimedon queenslandica (sponge), a member of an earliest diverging metazoan lineage (Porifera). Furthermore, phylogenetic comparisons of sponge GPCRs with eumetazoan and bilaterian GPCRs will be essential to our understanding of the GPCR system at the roots of metazoan evolution. Results: We present a curated list of 220 GPCRs in the sponge genome after excluding incomplete sequences and false positives from our initial dataset of 282 predicted GPCR sequences obtained using Pfam search. Phylogenetic analysis reveals that the sponge genome contains members belonging to four of the five major GRAFS families including Glutamate (33), Rhodopsin (126), Adhesion (40) and Frizzled (3). Interestingly, the sponge Rhodopsin family sequences lack orthologous relationships with those found in eumetazoan and bilaterian lineages, since they clustered separately to form sponge specific groups in the phylogenetic analysis. This suggests that sponge Rhodopsins diverged considerably from that found in other basal metazoans. A few sponge Adhesions clustered basal to Adhesion subfamilies commonly found in most vertebrates, suggesting some Adhesion subfamilies may have diverged prior to the emergence of Bilateria. Furthermore, at least eight of the sponge Adhesion members have a hormone binding motif (HRM domain) in their N-termini, although hormones have yet to be identified in sponges. We also phylogenetically clarified that sponge has homologs of metabotropic glutamate (mGluRs) and GABA receptors. Conclusion: Our phylogenetic comparisons of sponge GPCRs with other metazoan genomes suggest that sponge contains a significantly diversified set of GPCRs. This is evident at the family/subfamily level comparisons for most GPCR families, in particular for the Rhodopsin family of GPCRs. In summary, this study provides a framework to perform future experimental and comparative studies to further verify and understand the roles of GPCRs that predates the divergence of bilaterian and eumetazoan lineages.
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