Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The Membrane Proteome: Evolution, Characteristics and Classification
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]

Membrane proteins are found in all kingdoms of life and are essential for cellular interactions with the environment. Although a large research effort have been put into this group many membrane proteins remains uncharacterized, both in terms of function and evolutionary history. We have estimated the component of α-helical membrane proteins within the human proteome; the membrane proteome. We found that the human membrane proteome make up 27% of all protein, which we could classify the majority of into 234 families and further into three major functional groups: receptors, transporters or enzymes. We extended this analysis by determining the membrane proteome of 24 organisms that covers all major groups of eukaryotes. This comprehensive membrane protein catalog of over 100,000 proteins was utilized to determine the evolutionary history of all membrane protein families throughout eukaryotes.  We also investigated the evolutionary history across eukaryotes of the antiviral Interferon induced transmembrane proteins (IFITM) and the G protein-coupled receptor (GPCR) superfamily in detail.  We identified ten novel human homologs to the IFITM proteins, which together with the known IFITMs forms a family that we call the Dispanins. Using phylogenetic analysis we show that the Dispanins first emerged in eukaryotes in a common ancestor of choanoflagellates and animals, and that the family later expanded in vertebrates into four subfamilies. The GPCR superfamily was mined across eukaryotic species and we present evidence for a common origin for four of the five main human GPCR families; Rhodopsin, Frizzled, Adhesion and Secretin in the cAMP receptor family that was found in non-metazoans and invertebrates, but has been lost in vertebrates. Here we present the first accurate estimation of the human proteome together with comprehensive functional and evolutionary classification and extend it to organisms that represents all major eukaryotic groups. Moreover, we identify a novel protein family, the Dispanins, which has an evolutionary history that has been formed by horizontal gene transfer from bacteria followed by expansions in the animal lineage. We also study the evolution of the GPCR superfamily throughout eukaryotic evolution and provide a comprehensive model of the evolution and relationship of these receptors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 35 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 818
Keyword [en]
Membrane proteins, Membrane proteome, molecular evolution, GPCRs, Dispanins, IFITM
National Category
Evolutionary Biology Bioinformatics and Systems Biology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-181986ISBN: 978-91-554-8484-2 (print)OAI: oai:DiVA.org:uu-181986DiVA: diva2:558429
Public defence
2012-11-16, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-10-26 Created: 2012-10-02 Last updated: 2013-01-23Bibliographically approved
List of papers
1. 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, 50- p.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
2. Evolution and characteristics of the membrane proteome
Open this publication in new window or tab >>Evolution and characteristics of the membrane proteome
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Membrane proteins are found in all kingdoms of life and have a diverse set of functions and occupy key roles in many biological systems.  The majority of integral membrane proteins span the membrane with one or more transmembrane alpha helices, which both anchors the protein in the membrane and is crucial for their role in cell-cell interactions and signaling over the membrane. Herein, we have determined all alpha helical transmembrane proteins from 24 complete eukaryotic proteomes, which spans the four eukaryotic super groups chromalveolates, plants, excavates and unikonts. Hence, for the first time we are able to investigate the evolutionary history of the membrane proteome. In total we identify 100 955 membrane proteins among the more than 400 000 investigated proteins. We are able to place 91% of the membrane proteins into candidate families using Markov clustering based on sequence similarity and Pfam protein family affiliation. We provide evidence that most of the transporter and enzyme family repertoire of present eukaryotes was present already in the last common ancestor of all eukaryotes. Moreover, we discuss the functional nature of loss and gain of membrane protein families across eukaryotes and provide a comprehensive resource of the evolutionary history of the human membrane proteome.

Keyword
Membrane proteins, membrane proteome, comparative genomics
National Category
Bioinformatics and Systems Biology Evolutionary Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-181981 (URN)
Available from: 2012-10-02 Created: 2012-10-02 Last updated: 2013-01-23
3. The Dispanins: A Novel Gene Family of Ancient Origin That Contains 14 Human Members
Open this publication in new window or tab >>The Dispanins: A Novel Gene Family of Ancient Origin That Contains 14 Human Members
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, e31961- p.Article in journal (Refereed) Published
Abstract [en]

The Interferon induced transmembrane proteins (IFITM) are a family of transmembrane proteins that is known to inhibit cell invasion of viruses such as HIV-1 and influenza. We show that the IFITM genes are a subfamily in a larger family of transmembrane (TM) proteins that we call Dispanins, which refers to a common 2TM structure. We mined the Dispanins in 36 eukaryotic species, covering all major eukaryotic groups, and investigated their evolutionary history using Bayesian and maximum likelihood approaches to infer a phylogenetic tree. We identified ten human genes that together with the known IFITM genes form the Dispanin family. We show that the Dispanins first emerged in eukaryotes in a common ancestor of choanoflagellates and metazoa, and that the family later expanded in vertebrates where it forms four subfamilies (A-D). Interestingly, we also find that the family is found in several different phyla of bacteria and propose that it was horizontally transferred to eukaryotes from bacteria in the common ancestor of choanoflagellates and metazoa. The bacterial and eukaryotic sequences have a considerably conserved protein structure. In conclusion, we introduce a novel family, the Dispanins, together with a nomenclature based on the evolutionary origin.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-174788 (URN)10.1371/journal.pone.0031961 (DOI)000302871500098 ()
Available from: 2012-05-29 Created: 2012-05-28 Last updated: 2017-12-07Bibliographically 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, 2471-2480 p.Article 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.

Keyword
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
5. The Origin of GPCRs: Identification of Mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in Fungi
Open this publication in new window or tab >>The Origin of GPCRs: Identification of Mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in Fungi
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, e29817- p.Article in journal (Refereed) Published
Abstract [en]

G protein-coupled receptors (GPCRs) in humans are classified into the five main families named Glutamate, Rhodopsin, Adhesion, Frizzled and Secretin according to the GRAFS classification. Previous results show that these mammalian GRAFS families are well represented in the Metazoan lineages, but they have not been shown to be present in Fungi. Here, we systematically mined 79 fungal genomes and provide the first evidence that four of the five main mammalian families of GPCRs, namely Rhodopsin, Adhesion, Glutamate and Frizzled, are present in Fungi and found 142 novel sequences between them. Significantly, we provide strong evidence that the Rhodopsin family emerged from the cAMP receptor family in an event close to the split of Opisthokonts and not in Placozoa, as earlier assumed. The Rhodopsin family then expanded greatly in Metazoans while the cAMP receptor family is found in 3 invertebrate species and lost in the vertebrates. We estimate that the Adhesion and Frizzled families evolved before the split of Unikonts from a common ancestor of all major eukaryotic lineages. Also, the study highlights that the fungal Adhesion receptors do not have N-terminal domains whereas the fungal Glutamate receptors have a broad repertoire of mammalian-like N-terminal domains. Further, mining of the close unicellular relatives of the Metazoan lineage, Salpingoeca rosetta and Capsaspora owczarzaki, obtained a rich group of both the Adhesion and Glutamate families, which in particular provided insight to the early emergence of the N-terminal domains of the Adhesion family. We identified 619 Fungi specific GPCRs across 79 genomes and revealed that Blastocladiomycota and Chytridiomycota phylum have Metazoan-like GPCRs rather than the GPCRs specific for Fungi. Overall, this study provides the first evidence of the presence of four of the five main GRAFS families in Fungi and clarifies the early evolutionary history of the GPCR superfamily.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-172159 (URN)10.1371/journal.pone.0029817 (DOI)000301070200052 ()
Available from: 2012-04-03 Created: 2012-04-02 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

fulltext(2232 kB)541 downloads
File information
File name FULLTEXT01.pdfFile size 2232 kBChecksum SHA-512
3834bffa95888ad3c92255e5110482caa745506ac22530b6ec5e7f6037b5bc0869b575a820780b0a21b5172cf217055a807644a8c5ae1ec55d57be68083a6c15
Type fulltextMimetype application/pdf