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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

Proteins identified in the Dual functions class. The figure shows the 47 proteins identified as having specific dual functions. All of the neurotransmitter gated ion channel (NGIC) proteins are presented here, which include 46 members that are characterized by being a transporter and having a TC number (1.A.-.-.-; alpha-type channel) as well as being identified as a receptor. The NGIC are divided into their five different protein families, and the number of proteins identified as drug targets and the drug indications are presented. In addition, one protein is determined to be both an enzyme and transporter and the information is presented in the bottom row of the figure. The drug target and drug indications were identified through an updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation. The gene-disease associations for all NGIC proteins are also displayed. 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). The number in parenthesis represents the number of proteins that have been identified
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Fig4: Proteins identified in the Dual functions class. The figure shows the 47 proteins identified as having specific dual functions. All of the neurotransmitter gated ion channel (NGIC) proteins are presented here, which include 46 members that are characterized by being a transporter and having a TC number (1.A.-.-.-; alpha-type channel) as well as being identified as a receptor. The NGIC are divided into their five different protein families, and the number of proteins identified as drug targets and the drug indications are presented. In addition, one protein is determined to be both an enzyme and transporter and the information is presented in the bottom row of the figure. The drug target and drug indications were identified through an updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation. The gene-disease associations for all NGIC proteins are also displayed. 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). The number in parenthesis represents the number of proteins that have been identified

Mentions: Forty-seven proteins are distinguished as having dual functions as either receptor/transporter (46 proteins) or enzyme/transporter (1 protein) (Fig. 4). The complete repertoire of the 4TM neurotransmitter gated ion channel family, also known as the anionic and cationic cys-loop receptor group, includes all 45 proteins that belong to four different families as well as the single zinc activated ligand-gated ion channel protein [SwissProt: Q401N2]. The four families include gamma-aminobutryic-acid (GABAA), glycine, 5-hydroxytryptamine-3 (5HT3), and acetylcholine (nAChR) receptors and each protein contains the conserved neurotransmitter ligand binding domain (PF02931) as well as the ion channel domain (PF02932). All 46 NGIC proteins are described with a TC number as well as being identified as a receptor. In addition, these proteins are characterized by extracellular N- and C-termini. Thirty-five of the proteins are identified as drug targets which include a range of indications, as shown in Fig. 4. The common disease conditions include neurological diseases such as epilepsy, autistic disorder, schizophrenia, Alzheimer’s disease, various dependencies, as well as different cancers.Fig. 4


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)

Proteins identified in the Dual functions class. The figure shows the 47 proteins identified as having specific dual functions. All of the neurotransmitter gated ion channel (NGIC) proteins are presented here, which include 46 members that are characterized by being a transporter and having a TC number (1.A.-.-.-; alpha-type channel) as well as being identified as a receptor. The NGIC are divided into their five different protein families, and the number of proteins identified as drug targets and the drug indications are presented. In addition, one protein is determined to be both an enzyme and transporter and the information is presented in the bottom row of the figure. The drug target and drug indications were identified through an updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation. The gene-disease associations for all NGIC proteins are also displayed. 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). The number in parenthesis represents the number of proteins that have been identified
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4815072&req=5

Fig4: Proteins identified in the Dual functions class. The figure shows the 47 proteins identified as having specific dual functions. All of the neurotransmitter gated ion channel (NGIC) proteins are presented here, which include 46 members that are characterized by being a transporter and having a TC number (1.A.-.-.-; alpha-type channel) as well as being identified as a receptor. The NGIC are divided into their five different protein families, and the number of proteins identified as drug targets and the drug indications are presented. In addition, one protein is determined to be both an enzyme and transporter and the information is presented in the bottom row of the figure. The drug target and drug indications were identified through an updated dataset of all current targeted and potential proteins and genes involved in drug studies or experimentation. The gene-disease associations for all NGIC proteins are also displayed. 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). The number in parenthesis represents the number of proteins that have been identified
Mentions: Forty-seven proteins are distinguished as having dual functions as either receptor/transporter (46 proteins) or enzyme/transporter (1 protein) (Fig. 4). The complete repertoire of the 4TM neurotransmitter gated ion channel family, also known as the anionic and cationic cys-loop receptor group, includes all 45 proteins that belong to four different families as well as the single zinc activated ligand-gated ion channel protein [SwissProt: Q401N2]. The four families include gamma-aminobutryic-acid (GABAA), glycine, 5-hydroxytryptamine-3 (5HT3), and acetylcholine (nAChR) receptors and each protein contains the conserved neurotransmitter ligand binding domain (PF02931) as well as the ion channel domain (PF02932). All 46 NGIC proteins are described with a TC number as well as being identified as a receptor. In addition, these proteins are characterized by extracellular N- and C-termini. Thirty-five of the proteins are identified as drug targets which include a range of indications, as shown in Fig. 4. The common disease conditions include neurological diseases such as epilepsy, autistic disorder, schizophrenia, Alzheimer’s disease, various dependencies, as well as different cancers.Fig. 4

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