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Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome.

Attwood MM, Krishnan A, Pivotti V, Yazdi S, Almén MS, Schiöth HB - BMC Genomics (2016)

Bottom Line: From a structural perspective, the α-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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593, 751 24, Uppsala, Sweden.

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 α-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 ~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.

No MeSH data available.


Related in: MedlinePlus

The human 4TM Transporter class. The figure shows the 66 proteins of the Transporter class that are further categorized into seven different subclasses. The Transporter Classification number (TC) is determined by the Transporter Classification Database, which has been cross-referenced through Uniprot to obtain the TC number associated with the protein. The TC system is specific for membrane transport proteins and includes both functional and phylogenetic information in the numbering information. The transporter proteins identified as drug targets and the drug indications are also presented. An updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation was used to identify proteins that are drug targets as well as the drug indications. In addition, the top common gene-disease associations are displayed for each subgroup, with the number of proteins involved in parenthesis. Three different resources were used to identify gene-disease associations: the Online Mendelian Inheritance in Man (OMIM) database; the Functional Disease Ontology (FunDO) resource; and the Jensen Lab Diseases database (see Methods for details). Proteins that participate in transport activity but do not have an associated TC number are not included in this class, but rather in a subgroup of the Miscellaneous proteins. The number in parenthesis represents the number of proteins that have been identified in that group
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Fig2: The human 4TM Transporter class. The figure shows the 66 proteins of the Transporter class that are further categorized into seven different subclasses. The Transporter Classification number (TC) is determined by the Transporter Classification Database, which has been cross-referenced through Uniprot to obtain the TC number associated with the protein. The TC system is specific for membrane transport proteins and includes both functional and phylogenetic information in the numbering information. The transporter proteins identified as drug targets and the drug indications are also presented. An updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation was used to identify proteins that are drug targets as well as the drug indications. In addition, the top common gene-disease associations are displayed for each subgroup, with the number of proteins involved in parenthesis. Three different resources were used to identify gene-disease associations: the Online Mendelian Inheritance in Man (OMIM) database; the Functional Disease Ontology (FunDO) resource; and the Jensen Lab Diseases database (see Methods for details). Proteins that participate in transport activity but do not have an associated TC number are not included in this class, but rather in a subgroup of the Miscellaneous proteins. The number in parenthesis represents the number of proteins that have been identified in that group

Mentions: The Transporter category is the largest functional group with 66 proteins that are further divided into seven different classes (Fig. 2). Proteins identified with a Transport Classification number (TC) are included in this functional class. The alpha-type channel (TCDB ID: 1.A.-.-.) is the largest group and contains 26 proteins. Alpha-type channels transport solutes such as potassium, calcium, sodium, and chloride ions through transmembrane pores or channels via an energy-independent process [27]. Eight of these proteins function as subunits in gap junctions, where six are connexins and two are pannexins. There are two proteins within this group that are identified as drug targets: B-lymphocyte antigen CD20 [SwissProt: P11836] is involved in the regulation of B-cell activation and proliferation; and Calcium release-activated calcium channel protein 1 [SwissProt: Q96D31] which mediates calcium influx following depletion of calcium stores [28]. Sixteen genes in the alpha-type channel proteins are identified in various disease conditions and several of the most common disorders are displayed in Fig. 2. For a complete overview of the dataset including gene-disease associations, see Additional file 1.Fig. 2


Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome.

Attwood MM, Krishnan A, Pivotti V, Yazdi S, Almén MS, Schiöth HB - BMC Genomics (2016)

The human 4TM Transporter class. The figure shows the 66 proteins of the Transporter class that are further categorized into seven different subclasses. The Transporter Classification number (TC) is determined by the Transporter Classification Database, which has been cross-referenced through Uniprot to obtain the TC number associated with the protein. The TC system is specific for membrane transport proteins and includes both functional and phylogenetic information in the numbering information. The transporter proteins identified as drug targets and the drug indications are also presented. An updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation was used to identify proteins that are drug targets as well as the drug indications. In addition, the top common gene-disease associations are displayed for each subgroup, with the number of proteins involved in parenthesis. Three different resources were used to identify gene-disease associations: the Online Mendelian Inheritance in Man (OMIM) database; the Functional Disease Ontology (FunDO) resource; and the Jensen Lab Diseases database (see Methods for details). Proteins that participate in transport activity but do not have an associated TC number are not included in this class, but rather in a subgroup of the Miscellaneous proteins. The number in parenthesis represents the number of proteins that have been identified in that group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4815072&req=5

Fig2: The human 4TM Transporter class. The figure shows the 66 proteins of the Transporter class that are further categorized into seven different subclasses. The Transporter Classification number (TC) is determined by the Transporter Classification Database, which has been cross-referenced through Uniprot to obtain the TC number associated with the protein. The TC system is specific for membrane transport proteins and includes both functional and phylogenetic information in the numbering information. The transporter proteins identified as drug targets and the drug indications are also presented. An updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation was used to identify proteins that are drug targets as well as the drug indications. In addition, the top common gene-disease associations are displayed for each subgroup, with the number of proteins involved in parenthesis. Three different resources were used to identify gene-disease associations: the Online Mendelian Inheritance in Man (OMIM) database; the Functional Disease Ontology (FunDO) resource; and the Jensen Lab Diseases database (see Methods for details). Proteins that participate in transport activity but do not have an associated TC number are not included in this class, but rather in a subgroup of the Miscellaneous proteins. The number in parenthesis represents the number of proteins that have been identified in that group
Mentions: The Transporter category is the largest functional group with 66 proteins that are further divided into seven different classes (Fig. 2). Proteins identified with a Transport Classification number (TC) are included in this functional class. The alpha-type channel (TCDB ID: 1.A.-.-.) is the largest group and contains 26 proteins. Alpha-type channels transport solutes such as potassium, calcium, sodium, and chloride ions through transmembrane pores or channels via an energy-independent process [27]. Eight of these proteins function as subunits in gap junctions, where six are connexins and two are pannexins. There are two proteins within this group that are identified as drug targets: B-lymphocyte antigen CD20 [SwissProt: P11836] is involved in the regulation of B-cell activation and proliferation; and Calcium release-activated calcium channel protein 1 [SwissProt: Q96D31] which mediates calcium influx following depletion of calcium stores [28]. Sixteen genes in the alpha-type channel proteins are identified in various disease conditions and several of the most common disorders are displayed in Fig. 2. For a complete overview of the dataset including gene-disease associations, see Additional file 1.Fig. 2

Bottom Line: From a structural perspective, the α-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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593, 751 24, Uppsala, Sweden.

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 α-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 ~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.

No MeSH data available.


Related in: MedlinePlus