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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 Enzyme class. The figure displays the 45 proteins identified with an EC number that belong to the Enzyme class. The enzymes are divided into five groups which correspond to the type of chemical reaction that they catalyze. Uniprot cross-references the ENZYME nomenclature database and IntEnz (Integrated relational Enzyme database) to obtain the EC number associated with a protein. The single protein classified as a drug target as well as the drug indications are displayed. 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. Some of the most common gene-disease associations are also shown for each of the subgroups in the Enzyme class. 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 are involved in enzymatic activity but do not have an associated EC 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
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Fig3: The human 4TM Enzyme class. The figure displays the 45 proteins identified with an EC number that belong to the Enzyme class. The enzymes are divided into five groups which correspond to the type of chemical reaction that they catalyze. Uniprot cross-references the ENZYME nomenclature database and IntEnz (Integrated relational Enzyme database) to obtain the EC number associated with a protein. The single protein classified as a drug target as well as the drug indications are displayed. 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. Some of the most common gene-disease associations are also shown for each of the subgroups in the Enzyme class. 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 are involved in enzymatic activity but do not have an associated EC 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

Mentions: The Enzyme class includes 45 proteins with a corresponding Enzyme Commission (EC) number (Fig. 3). Oxidoreductases (EC 1.-.-.-) that catalyze oxidation/reduction reactions in which H and O atoms or electrons are transferred from one substance to another include 12 enzymes. There are varied specific functions within this group, including iron ion binding and lipid metabolic processes [28]. Transferases (EC 2.-.-.-) are the largest enzymatic group with 25 proteins, and 18 of these contain the zf-DHHC palmitoyltransferase functional domain (PF01529) which is involved in zinc as well as other ion binding [31]. While there are 23 mammalian DHHC proteins identified in the membrane proteome [32], only 18 of them are predicted to have 4TMs. There are two proteins described as hydrolases (EC 3.-.-.-), which use hydrolysis to form two products. Three proteins are lyases (EC 4.-.-.-) and two of these contain the Protein tyrosine phosphatase-like protein domain (PF04387) which functions in very long chain fatty acid biosynthesis [31]. All three lyases are involved in a variety of disease conditions. And three proteins are classified as ligases (EC 6.-.-.-) in which all are involved as E3 ubiquitin ligases.Fig. 3


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 Enzyme class. The figure displays the 45 proteins identified with an EC number that belong to the Enzyme class. The enzymes are divided into five groups which correspond to the type of chemical reaction that they catalyze. Uniprot cross-references the ENZYME nomenclature database and IntEnz (Integrated relational Enzyme database) to obtain the EC number associated with a protein. The single protein classified as a drug target as well as the drug indications are displayed. 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. Some of the most common gene-disease associations are also shown for each of the subgroups in the Enzyme class. 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 are involved in enzymatic activity but do not have an associated EC 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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4815072&req=5

Fig3: The human 4TM Enzyme class. The figure displays the 45 proteins identified with an EC number that belong to the Enzyme class. The enzymes are divided into five groups which correspond to the type of chemical reaction that they catalyze. Uniprot cross-references the ENZYME nomenclature database and IntEnz (Integrated relational Enzyme database) to obtain the EC number associated with a protein. The single protein classified as a drug target as well as the drug indications are displayed. 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. Some of the most common gene-disease associations are also shown for each of the subgroups in the Enzyme class. 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 are involved in enzymatic activity but do not have an associated EC 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
Mentions: The Enzyme class includes 45 proteins with a corresponding Enzyme Commission (EC) number (Fig. 3). Oxidoreductases (EC 1.-.-.-) that catalyze oxidation/reduction reactions in which H and O atoms or electrons are transferred from one substance to another include 12 enzymes. There are varied specific functions within this group, including iron ion binding and lipid metabolic processes [28]. Transferases (EC 2.-.-.-) are the largest enzymatic group with 25 proteins, and 18 of these contain the zf-DHHC palmitoyltransferase functional domain (PF01529) which is involved in zinc as well as other ion binding [31]. While there are 23 mammalian DHHC proteins identified in the membrane proteome [32], only 18 of them are predicted to have 4TMs. There are two proteins described as hydrolases (EC 3.-.-.-), which use hydrolysis to form two products. Three proteins are lyases (EC 4.-.-.-) and two of these contain the Protein tyrosine phosphatase-like protein domain (PF04387) which functions in very long chain fatty acid biosynthesis [31]. All three lyases are involved in a variety of disease conditions. And three proteins are classified as ligases (EC 6.-.-.-) in which all are involved as E3 ubiquitin ligases.Fig. 3

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