Dataset Information

Phylogenetic and conservation analyses of MFS transporters.

ABSTRACT: Major facilitator superfamily is one of the largest superfamily of secondary transporters present across the kingdom of life. Considering the physiological and clinical importance of MFS proteins, we attempted to explore the phylogenetic and structural aspects of the superfamily. To achieve the objectives, we performed global sequence-based analyses of MFS proteins encompassing multiple taxa. Notably, phylogenetic analysis of MFS proteins resulted in the clustering of MFS proteins based on their function, rather than lineage of the respective organisms. Additionally, we employed information theoretic measures, Relative entropy (RE) and Cumulative relative entropy (CRE) to decipher fold-specific and function-specific residues, respectively, in the MFS proteins. The residues with high RE score when mapped on to the 3D-structure of MFS transporter LacY, were found to be distributed throughout the tertiary structure of the protein. On the other hand, CRE calculation was employed to contrast two subfamilies Drug H+ antiporter 1 and 3 (DHA1 and DHA3). The particular analysis unveiled certain differentially conserved residues in DHA1 as compared to DHA3 highlighting family-specific importance of them. Remarkably, a number of high scoring CRE residues have already established functional roles, for instance, the arginine residue present in TMH4. Altogether, the current study apart from providing an insight into the functional clustering of MFS proteins also identifies residues with established or plausible roles in the transport mechanism. Thus, the study lays a platform for future structure-function studies of these proteins.

SUBMITTER: Vishwakarma P

PROVIDER: S-EPMC6204130 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Phylogenetic and conservation analyses of MFS transporters.

Vishwakarma Poonam P Banerjee Atanu A Pasrija Ritu R Prasad Rajendra R Lynn Andrew M AM

3 Biotech 20181027 11

Major facilitator superfamily is one of the largest superfamily of secondary transporters present across the kingdom of life. Considering the physiological and clinical importance of MFS proteins, we attempted to explore the phylogenetic and structural aspects of the superfamily. To achieve the objectives, we performed global sequence-based analyses of MFS proteins encompassing multiple taxa. Notably, phylogenetic analysis of MFS proteins resulted in the clustering of MFS proteins based on their ...[more]

PMID: 30370203

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Project description:In yeasts, proteins of the Major Superfamily Transporter selectively bind and allow the uptake of sugars to permit growth on varied substrates. The genome of brewer's yeast, Saccharomyces cerevisiae, encodes multiple hexose transporters (Hxt) to transport glucose and other MFS proteins for maltose, galactose, and other monomers. For sugar uptake, the dairy yeast, Kluyveromyces lactis, uses Rag1p for glucose, Hgt1 for glucose and galactose, and Lac12 for lactose. In the related industrial species Kluyveromyces marxianus, there are four genes encoding Lac12-like proteins but only one of them, Lac12, can transport lactose. In this study, which initiated with efforts to investigate possible functions encoded by the additional LAC12 genes in K. marxianus, a genome-wide survey of putative MFS sugar transporters was performed. Unexpectedly, it was found that the KHT and the HGT genes are present as tandem arrays of five to six copies, with the precise number varying between isolates. Heterologous expression of individual genes in S. cerevisiae and mutagenesis of single and multiple genes in K. marxianus was performed to establish possible substrates for these transporters. The focus was on the sugar galactose since it was already reported in K. lactis that this hexose was a substrate for both Lac12 and Hgt1. It emerged that three of the four copies of Lac12, four Hgt-like proteins and one Kht-like protein have some capacity to transport galactose when expressed in S. cerevisiae and inactivation of all eight genes was required to completely abolish galactose uptake in K. marxianus. Analysis of the amino acid sequence of all known yeast galactose transporters failed to identify common residues that explain the selectivity for galactose. Instead, the capacity to transport galactose has arisen three different times in K. marxianus via polymorphisms in proteins that are probably ancestral glucose transporters. Although, this is analogous to S. cerevisiae, in which Gal2 is related to glucose transporters, there are not conserved amino acid changes, either with Gal2, or among the K. marxianus galactose transporters. The data highlight how gene duplication and functional diversification has provided K. marxianus with versatile capacity to utilise sugars for growth.

Project description:The monovalent anions formate, nitrite and hydrosulphide are main metabolites of bacterial respiration during anaerobic mixed-acid fermentation. When accumulated in the cytoplasm, these anions become cytotoxic. Membrane proteins that selectively transport these monovalent anions across the membrane have been identified and they belong to the family of Formate/Nitrite Transporters (FNTs). Individual members that selectively transport formate, nitrite and hydrosulphide have been investigated. Experimentally determined structures of FNTs indicate that they share the same hourglass helical fold with aquaporins and aquaglyceroporins and have two constriction regions, namely, cytoplasmic slit and central constriction. Members of FNTs are found in bacteria, archaea, fungi and protists. However, no FNT homolog has been identified in mammals. With FNTs as potential drug targets for many bacterial diseases, it is important to understand the mechanism of selectivity and transport across these transporters.We have systematically searched the sequence databases and identified 2206 FNT sequences from bacteria, archaea and eukaryotes. Although FNT sequences are very diverse, homology modeling followed by structure-based sequence alignment revealed that nearly one third of all the positions within the transmembrane region exhibit high conservation either as a group or at the level of individual residues across all three kingdoms. Phylogenetic analysis of prokaryotic FNT sequences revealed eight different subgroups. Formate, nitrite and hydrosulphide transporters respectively are clustered into two (FocA and FdhC), three (NirC-?, NirC-? and NirC-?) and one (HSC) subfamilies. We have also recognized two FNT subgroups (YfdC-? and YfdC-?) with unassigned function. Analysis of taxonomic distribution indicates that each subfamily prefers specific taxonomic groups. Structure-based sequence alignment of individual subfamily members revealed that certain positions in the two constriction regions and some residues facing the interior show subfamily-specific conservation. We have also identified examples of FNTs with the two constriction regions formed by residues that are less frequently observed. We have developed dbFNT, a database of FNT models and associated details. dbFNT is freely available to scientific community.Taxonomic distribution and sequence conservation of FNTs exhibit subfamily-specific features. The conservation pattern in the central constriction and cytoplasmic slit in the open and closed states are distinct for YfdC and NirC subfamilies. The same is true for some residues facing the interior of the transporters. The specific residues in these positions can exert influence on the type of solutes that are transported by these proteins. With FNTs found in many disease-causing bacteria, the knowledge gained in this study can be used in the development and design of anti-bacterial drugs.

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Phylogenetic and conservation analyses of MFS transporters.

Publications

Phylogenetic and conservation analyses of MFS transporters.

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