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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

Functional classification breakdown within the 4TM major clans and families. The figure displays the breakdown of how many proteins within each major clan and family are identified for each functional class, i.e. Transporter, Enzyme, Dual function, Receptor, and Miscellaneous classes. Approximately 61 % of the dataset is described by these eight clans and families. The number in parenthesis corresponds to the total number of proteins within that clan or family
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Fig7: Functional classification breakdown within the 4TM major clans and families. The figure displays the breakdown of how many proteins within each major clan and family are identified for each functional class, i.e. Transporter, Enzyme, Dual function, Receptor, and Miscellaneous classes. Approximately 61 % of the dataset is described by these eight clans and families. The number in parenthesis corresponds to the total number of proteins within that clan or family

Mentions: There are eight major Pfam domain families and clans within the dataset that contain between 5–81 members (see Fig. 7): Transport superfamily clan (78 proteins), Tetraspanin-like clan (53 proteins), Marvel-like clan (24 proteins), Zinc beta ribbon clan (18 proteins), NGIC family (46 proteins), Reticulon family (7 proteins), L6-membrane family (6 proteins), and Got1/Sft2-like family (5 proteins). The clans are composed of homologous domain families and include the unique four-transmembrane protein families such as claudins, connexins and tetraspanins. The domain families are formed from the collection of proteins with the same conserved Pfam domain, such as the 46 members of the NGIC family, and which do not belong to any clan and thus do not have any identified homologous sister families.Fig. 7


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)

Functional classification breakdown within the 4TM major clans and families. The figure displays the breakdown of how many proteins within each major clan and family are identified for each functional class, i.e. Transporter, Enzyme, Dual function, Receptor, and Miscellaneous classes. Approximately 61 % of the dataset is described by these eight clans and families. The number in parenthesis corresponds to the total number of proteins within that clan or family
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Functional classification breakdown within the 4TM major clans and families. The figure displays the breakdown of how many proteins within each major clan and family are identified for each functional class, i.e. Transporter, Enzyme, Dual function, Receptor, and Miscellaneous classes. Approximately 61 % of the dataset is described by these eight clans and families. The number in parenthesis corresponds to the total number of proteins within that clan or family
Mentions: There are eight major Pfam domain families and clans within the dataset that contain between 5–81 members (see Fig. 7): Transport superfamily clan (78 proteins), Tetraspanin-like clan (53 proteins), Marvel-like clan (24 proteins), Zinc beta ribbon clan (18 proteins), NGIC family (46 proteins), Reticulon family (7 proteins), L6-membrane family (6 proteins), and Got1/Sft2-like family (5 proteins). The clans are composed of homologous domain families and include the unique four-transmembrane protein families such as claudins, connexins and tetraspanins. The domain families are formed from the collection of proteins with the same conserved Pfam domain, such as the 46 members of the NGIC family, and which do not belong to any clan and thus do not have any identified homologous sister families.Fig. 7

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