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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abramson J, Smirnova I, Kasho V et al (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301:610–615. https://doi.org/10.1126/science.1088196
Andersson M, Bondar AN, Freites JA et al (2012) Proton-coupled dynamics in lactose permease. Structure 20:1893–1904. https://doi.org/10.1016/j.str.2012.08.021
Bannam TL, Johanesen PA, Salvado CL et al (2004) The Clostridium perfringens TetA(P) efflux protein contains a functional variant of the Motif A region found in major facilitator superfamily transport proteins. Microbiology 150:127–134. https://doi.org/10.1099/mic.0.26614-0
Bley C, van der Linden M, Reinert RR (2011) mef(A) is the predominant macrolide resistance determinant in Streptococcus pneumoniae and Streptococcus pyogenes in Germany. Int J Antimicrob Agents 37:425–431. https://doi.org/10.1016/j.ijantimicag.2011.01.019
Crooks GE, Hon G, Chandonia J-M, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14:1188–1190. https://doi.org/10.1101/gr.849004
Deng D, Xu C, Sun P et al (2014) Crystal structure of the human glucose transporter GLUT1. Nature 510:121–125. https://doi.org/10.1038/nature13306
Diallinas G (2016) Dissection of transporter function: from genetics to structure. Trends Genet 32:576–590. https://doi.org/10.1016/j.tig.2016.06.003
Edgar R, Bibi E (1997) MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition. J Bacteriol 179:2274 LP–L2280
Finn RD, Coggill P, Eberhardt RY et al (2016) The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res 44:D279–D285. https://doi.org/10.1093/nar/gkv1344
Forrest LR, Krämer R, Ziegler C (2011) The structural basis of secondary active transport mechanisms. Biochim Biophys Acta Bioenerg 1807:167–188. https://doi.org/10.1016/j.bbabio.2010.10.014
Gaur M, Puri N, Manoharlal R et al (2008) MFS transportome of the human pathogenic yeast Candida albicans. BMC Genom 9:579. https://doi.org/10.1186/1471-2164-9-579
Guan L, Kaback HR (2006) Lessons from lactose permease. Annu Rev Biophys Biomol Struct 35:67–91. https://doi.org/10.1146/annurev.biophys.35.040405.102005
Heng J, Zhao Y, Liu M et al (2015) Substrate-bound structure of the E. coli multidrug resistance transporter MdfA. Cell Res 25:1060
Huang Y, Lemieux MJ, Song J et al (2003) Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301:616–620. https://doi.org/10.1126/science.1087619
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:27–28,33–38
Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211:969–970
Jiang X, Smirnova I, Kasho V et al (2016) Crystal structure of a LacY-nanobody complex in a periplasmic-open conformation. Proc Natl Acad Sci USA 113:12420–12425. https://doi.org/10.1073/pnas.1615414113
Jung K, Jung H, Colacurcio P, Kaback HR (1995) Role of glycine residues in the structure and function of lactose permease, an Escherichia coli membrane transport protein. Biochemistry 34:1030–1039. https://doi.org/10.1021/bi00003a038
Kaback HR, Smirnova I, Kasho V et al (2011) The alternating access transport mechanism in LacY. J Membr Biol 239:85–93. https://doi.org/10.1007/s00232-010-9327-5
Kapoor K, Rehan M, Lynn AM, Prasad R (2010) Employing information theoretic measures and mutagenesis to identify residues critical for drug-proton antiport function in mdr1p of Candida albicans. PLoS One. https://doi.org/10.1371/journal.pone.0011041
Kasho VN, Smirnova IN, Kaback HR (2006) Sequence alignment and homology threading reveals prokaryotic and eukaryotic proteins similar to lactose permease. J Mol Biol 358:1060–1070. https://doi.org/10.1016/j.jmb.2006.02.049
Katoh K, Standley DM (2013) MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30:772–780. https://doi.org/10.1093/molbev/mst010
Katoh K, Misawa K, Kuma K, Miyata T (2002) MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res 30:3059–3066
Klauda JB, Brooks BR (2007) Sugar binding in lactose permease: anomeric state of a disaccharide influences binding structure. J Mol Biol 367:1523–1534. https://doi.org/10.1016/j.jmb.2007.02.001
Kullback S, Leibler RA (1951) On information and sufficiency. Ann Math Stat 28:89–110
Kumar H, Finer-Moore JS, Jiang X et al (2018) Crystal structure of a ligand-bound LacY-nanobody complex. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1801774115
Lee J, Sands ZA, Biggin PC (2016) A numbering system for MFS transporter proteins. Front Mol Biosci 3:1–13. https://doi.org/10.3389/fmolb.2016.00021
Nagata S, Imai J, Makino G et al (2017) Evolutionary analysis of HIV-1 pol proteins reveals representative residues for viral subtype differentiation. Front Microbiol 8:2151. https://doi.org/10.3389/fmicb.2017.02151
Pedersen BP, Kumar H, Waight AB et al (2013) Crystal structure of a eukaryotic phosphate transporter. Nature 496:533–536. https://doi.org/10.1038/nature12042
Pirovano W, Feenstra KA, Heringa J (2008) PRALINE™: a strategy for improved multiple alignment of transmembrane proteins. Bioinformatics 24:492–497. https://doi.org/10.1093/bioinformatics/btm636
Price MN, Dehal PS, Arkin AP (2009) FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol Biol Evol 26:1641–1650. https://doi.org/10.1093/molbev/msp077
Redhu AK, Shah AH, Prasad R (2016a) MFS transporters of Candida species and their role in clinical drug resistance. FEMS Yeast Res 16:1–12. https://doi.org/10.1093/femsyr/fow043
Redhu AK, Banerjee A, Shah AH et al (2018) Molecular basis of substrate polyspecificity of the Candida albicans Mdr1p multidrug/H(+) antiporter. J Mol Biol 430:682–694. https://doi.org/10.1016/j.jmb.2018.01.005
Russell RB, Barton GJ (1992) Multiple protein sequence alignment from tertiary structure comparison: assignment of global and residue confidence levels. Proteins 14:309–323. https://doi.org/10.1002/prot.340140216
Saier MH, Reddy VS, Tamang DG, Västermark Å (2014) The transporter classification database. Nucleic Acids Res 42:D251–D258. https://doi.org/10.1093/nar/gkt1097
Sanglard D, Kuchler K, Ischer F et al (1995) Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother 39:2378–2386. https://doi.org/10.1128/AAC.39.11.2378
Schneider TD, Stephens RM (1990) Sequence logos: a new way to display consensus sequences. Nucleic Acids Res 18:6097–6100. https://doi.org/10.1093/nar/18.20.6097
Shi Y (2013) Common folds and transport mechanisms of secondary active transporters. Annu Rev Biophys 42:51–72. https://doi.org/10.1146/annurev-biophys-083012-130429
Suárez-Germà C, Loura LMS, Domènech Ò et al (2012) Phosphatidylethanolamine–lactose permease interaction: a comparative study based on FRET. J Phys Chem B 116:14023–14028. https://doi.org/10.1021/jp309726v
Sun L, Zeng X, Yan C et al (2012) Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 490:361–366. https://doi.org/10.1038/nature11524
Sun J, Bankston JR, Payandeh J et al (2014) Crystal structure of the plant dual-affinity nitrate transporter NRT1.1. Nature 507:73
Tsirigos KD, Peters C, Shu N et al (2015) The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides. Nucleic Acids Res 43:W401–W407. https://doi.org/10.1093/nar/gkv485
Varela MF, Sansom CE, Griffith JK (1995) Mutational analysis and molecular modelling of an amino acid sequence motif conserved in antiporters but not symporters in a transporter superfamily. Mol Membr Biol 12:313–319
Weinglass AB, Kaback HR (1999) Conformational flexibility at the substrate binding site in the lactose permease of Escherichia coli. 96:11178–11182
White TC (1997) Increased mRNA levels of ERG16, CDR, and MDR1 correlate, with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob Agents Chemother 41:1482–1487
Yan N (2013) Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem Sci 38:151–159. https://doi.org/10.1016/j.tibs.2013.01.003
Yan N (2015) Structural biology of the major facilitator superfamily transporters. Annu Rev Biophys 44:257–283. https://doi.org/10.1146/annurev-biophys-060414-033901
Yin Y, He X, Szewczyk P et al (2006) Structure of the multidrug transporter EmrD from Escherichia coli. Science 312:741–744. https://doi.org/10.1126/science.1125629
Zhang XC, Zhao Y, Heng J, Jiang D (2015) Energy coupling mechanisms of MFS transporters. Protein Sci 24:1560–1579. https://doi.org/10.1002/pro.2759
Zhuang X, Klauda JB (2016) Modeling structural transitions from the periplasmic-open state of lactose permease and interpretations of spin label experiments. Biochim Biophys Acta Biomembr 1858:1541–1552. https://doi.org/10.1016/j.bbamem.2016.04.008
Acknowledgements
The authors would like to thank HPCF facility of SC & IS, JNU for providing computational facility. PV would like to acknowledge UPE-II (project ID 105) for financial support.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors would like to declare that no conflicts of interest exist.
Rights and permissions
About this article
Cite this article
Vishwakarma, P., Banerjee, A., Pasrija, R. et al. Phylogenetic and conservation analyses of MFS transporters. 3 Biotech 8, 462 (2018). https://doi.org/10.1007/s13205-018-1476-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13205-018-1476-8