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Evolution of Membrane Bound Proteins and their Ligands: The Melanocortin (MC) Receptor Inverse Agonists AgRP2, ASIP2, Drug/Metabolite Transporters, and SPNS1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Integral membrane proteins play a key role hormonal and neuronal signaling. Transmembrane helix (TM) proteins form about 27% of the human proteome. Furthermore, 44% of the human drug targets are receptors, and 19% of these are seven-transmembrane domain receptors (GPCRs), which constitute 4% of the entire protein-coding genome. After receptors, solute carriers (SLCs) constitute the second largest superfamily of TM proteins. Three of the largest SLC families contain protein domains that are members of the drug/metabolite transporter clan.

We present evidence that the drug/metabolite transporter (DMT) families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. We renamed several transporters, and introduced the new HGNC-approved nomenclature of SLC35G1 – 6.

We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Holocephali. However, we do not find any of these genes in lamprey or lancelet, suggesting that the MCA and MCB receptors function without antagonists in lamprey.

We report that a venom peptide in Plectreurys tristis has the same cysteine knot structure as fish AgRP2, a higher similarity than previously known. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is likely to be the most ancestral, first splitting from a common ancestor to ASIP and A2. We introduce a new technique for synteny detection, sinusoidal Hough transform.

We found that the known obesity SNPs in SH2B1, rs4788102 (p=0.0023) and rs7498665 (p=0.0018) were associated with triglyceride levels in the North Swedish Population Health Study (NSPHS) cohort, consisting of 719 individuals from the Karesuando parish in northern Sweden. To account for kinship, the SH2B1 SNPs, and four SNPs in the expanded region were analyzed for association with triglyceride levels using SOLAR. We found a stronger signal (p=0.0009) for a SNP, near SH2B1, rs8045689, located in an intron of SPNS1 which is structurally similar to a sphingolipid transporter.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 789
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-177650ISBN: 978-91-554-8407-1 (print)OAI: oai:DiVA.org:uu-177650DiVA, id: diva2:541358
Public defence
2012-09-06, C8:305, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-08-15 Created: 2012-07-17 Last updated: 2013-01-22Bibliographically approved
List of papers
1. Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae
Open this publication in new window or tab >>Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae
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2011 (English)In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 11, p. 123-Article in journal (Refereed) Published
Abstract [en]

Background: The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families. Results: We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. Conclusions: The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

Keywords
SLC30 SLC35, SLC39, drug/metabolite transporters, nucleotide sugar transporters, EamA, EmrE, multi drug resistance protein, dual-topology proteins, transmembrane helix
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-155600 (URN)10.1186/1471-2148-11-123 (DOI)000291406500001 ()
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2018-01-12Bibliographically approved
2. Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden
Open this publication in new window or tab >>Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden
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2012 (English)In: Journal of Genetics, ISSN 0022-1333, E-ISSN 0973-7731, Vol. 91, no 2, p. 237-240Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Springer: , 2012
Keywords
Karesuando; NSPHS; SH2B1 gene; SPNS1; triglycerides; SOLAR.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-177647 (URN)10.1007/s12041-012-0167-1 (DOI)000308363400017 ()
Available from: 2012-07-17 Created: 2012-07-17 Last updated: 2017-12-07Bibliographically approved
3.
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4. The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus
Open this publication in new window or tab >>The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus
2011 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 660, no 1, p. 61-69Article in journal (Refereed) Published
Abstract [en]

There are conflicting theories about the evolution of melanocortin MC receptors while only few studies have addressed the evolution of agouti-related peptide (AgRP) and agouti signalling peptide (ASIP), which are antagonists at the melanocortin receptors (MCRs), or the melanocortin MC(2) receptor accessory proteins (MRAP1 and MRAP2). Previously we have cloned melanocortin MC receptors (MC(a) and MC(b)) genes in river lamprey and here we identify orthologues to these melanocortin MC receptor sequences in the sea lamprey. We investigate the putative presence of the melanocortin MC receptor genes in lancelet (amphioxus; Branchiostoma floridae) but we find it unlikely that such gene exists, due to a sharp drop in sequence similarity beyond sequence clusters of known receptors. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Elasmobranchii. However, we do not find any of these genes in lamprey or lancelet after detailed analysis of both targeted and whole proteome regular expression scans. We found MRAP2, but not MRAP1, to be present in elephant shark and sea lamprey while Fugu (T. rubripes) has both genes. This study shows that the most ancient presence of these melanocortin-related sequences is found in elephant shark and lampreys considering the current available sequence data.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-146217 (URN)10.1016/j.ejphar.2010.10.106 (DOI)000291232200008 ()21208605 (PubMedID)
Available from: 2011-02-15 Created: 2011-02-15 Last updated: 2018-01-12Bibliographically approved

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