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PMID: 22458847 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The major facilitator superfamily (MFS) revisited.

The FEBS journal ·Vol. 279 ·No. 11 ·2012-06-00 ·Pages 2022-35

Reddy VS, Shlykov MA, Castillo R, Sun EI, Saier MH

Abstract

The major facilitator superfamily (MFS) is the largest known superfamily of secondary carriers found in the biosphere. It is ubiquitously distributed throughout virtually all currently recognized organismal phyla. This superfamily currently (2012) consists of 74 families, each of which is usually concerned with the transport of a certain type of substrate. Many of these families, defined phylogenetically, do not include even a single member that is functionally characterized. In this article, we probe the evolutionary origins of these transporters, providing evidence that they arose from a single 2-transmembrane segment (TMS) hairpin structure that triplicated to give a 6-TMS unit that duplicated to a 12-TMS protein, the most frequent topological type of these permeases. We globally examine MFS protein topologies, focusing on exceptional proteins that deviate from the norm. Nine distantly related families appear to have members with 14 TMSs in which the extra two are usually centrally localized between the two 6-TMS repeat units. They probably have arisen by intragenic duplication of an adjacent hairpin. This alternative topology probably arose multiple times during MFS evolution. Convincing evidence for MFS permeases with fewer than 12 TMSs was not forthcoming, leading to the suggestion that all 12 TMSs are required for optimal function. Some homologs appear to have 13, 14, 15 or 16 TMSs, and the probable locations of the extra TMSs were identified. A few MFS permeases are fused to other functional domains or are fully duplicated to give 24-TMS proteins with dual functions. Finally, the MFS families with no known function were subjected to genomic context analyses leading to functional predictions.

MeSH Terms
Amino Acid Sequence Bacterial Proteins/chemistry,genetics,metabolism Computational Biology Databases, Genetic Evolution, Molecular Inverted Repeat Sequences/genetics Membrane Transport Proteins/chemistry,genetics,metabolism Molecular Sequence Data Phylogeny Sequence Homology, Amino Acid Structure-Activity Relationship
Chemicals
Bacterial Proteins Membrane Transport Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Reddy Vamsee S
Division of Biological Sciences, University of California at San Diego, La Jolla, CA, USA.
Shlykov Maksim A
Castillo Rostislav
Sun Eric I
Saier Milton H
References (60)
60 references, click to expand
  1. Helices VII and X in the lactose permease of Escherichia coli: proximity and ligand-induced distance changes.
    J Mol Biol. 2002 Jan 4;315(1):53-62 PMID: 11771965
  2. A comprehensive set of sequence analysis programs for the VAX.
    Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387-95 PMID: 6546423
  3. TCDB: the Transporter Classification Database for membrane transport protein analyses and information.
    Nucleic Acids Res. 2006 Jan 1;34(Database issue):D181-6 PMID: 16381841
  4. The phagosomal nutrient transporter (Pht) family.
    Microbiology (Reading). 2008 Jan;154(Pt 1):42-53 PMID: 18174124
  5. Lysophospholipid flipping across the Escherichia coli inner membrane catalyzed by a transporter (LplT) belonging to the major facilitator superfamily.
    J Biol Chem. 2005 Mar 25;280(12):12028-34 PMID: 15661733
  6. Ins and outs of major facilitator superfamily antiporters.
    Annu Rev Microbiol. 2008;62:289-305 PMID: 18537473
  7. Bioinformatic characterization of the 4-Toluene Sulfonate Uptake Permease (TSUP) family of transmembrane proteins.
    Biochim Biophys Acta. 2012 Mar;1818(3):703-17 PMID: 22192777
  8. The Escherichia coli YdcF binds S-adenosyl-L-methionine and adopts an alpha/beta-fold characteristic of nucleotide-utilizing enzymes.
    Proteins. 2008 Jul;72(1):506-9 PMID: 18393394
  9. Proton-dependent multidrug efflux systems.
    Microbiol Rev. 1996 Dec;60(4):575-608 PMID: 8987357
  10. Sequence analyses of cyanobacterial bicarbonate transporters and their homologues.
    J Mol Microbiol Biotechnol. 2004;7(3):102-8 PMID: 15263814
  11. The subsystems approach to genome annotation and its use in the project to annotate 1000 genomes.
    Nucleic Acids Res. 2005 Oct 07;33(17):5691-702 PMID: 16214803
  12. Functional Promiscuity of Homologues of the Bacterial ArsA ATPases.
    Int J Microbiol. 2010;2010:187373 PMID: 20981284
  13. Bacterial multidrug transport through the lens of the major facilitator superfamily.
    Biochim Biophys Acta. 2009 May;1794(5):738-47 PMID: 19103310
  14. Principles governing amino acid composition of integral membrane proteins: application to topology prediction.
    J Mol Biol. 1998 Oct 23;283(2):489-506 PMID: 9769220
  15. Membrane porters of ATP-binding cassette transport systems are polyphyletic.
    J Membr Biol. 2009 Sep;231(1):1-10 PMID: 19806386
  16. Establishing homologies in protein sequences.
    Methods Enzymol. 1983;91:524-45 PMID: 6855599
  17. Phylogeny of multidrug transporters.
    Semin Cell Dev Biol. 2001 Jun;12(3):205-13 PMID: 11428913
  18. RegPredict: an integrated system for regulon inference in prokaryotes by comparative genomics approach.
    Nucleic Acids Res. 2010 Jul;38(Web Server issue):W299-307 PMID: 20542910
  19. Biosynthesis of D-arabinose in mycobacteria - a novel bacterial pathway with implications for antimycobacterial therapy.
    FEBS J. 2008 Jun;275(11):2691-711 PMID: 18422659
  20. Twelve-transmembrane-segment (TMS) version (DeltaTMS VII-VIII) of the 14-TMS Tet(L) antibiotic resistance protein retains monovalent cation transport modes but lacks tetracycline efflux capacity.
    J Bacteriol. 2001 Apr;183(8):2667-71 PMID: 11274128
  21. Structural determination of wild-type lactose permease.
    Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15294-8 PMID: 17881559
  22. Animal Ca2+ release-activated Ca2+ (CRAC) channels appear to be homologous to and derived from the ubiquitous cation diffusion facilitators.
    BMC Res Notes. 2010 Jun 03;3:158 PMID: 20525303
  23. A transporter of Escherichia coli specific for L- and D-methionine is the prototype for a new family within the ABC superfamily.
    Arch Microbiol. 2003 Aug;180(2):88-100 PMID: 12819857
  24. A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport.
    Trends Biochem Sci. 1993 Jan;18(1):13-20 PMID: 8438231
  25. A web-based program for the prediction of average hydropathy, average amphipathicity and average similarity of multiply aligned homologous proteins.
    J Mol Microbiol Biotechnol. 2001 Apr;3(2):285-6 PMID: 11321584
  26. The alternating-access mechanism of MFS transporters arises from inverted-topology repeats.
    J Mol Biol. 2011 Apr 15;407(5):698-715 PMID: 21315728
  27. Canonical and ECF-type ATP-binding cassette importers in prokaryotes: diversity in modular organization and cellular functions.
    FEMS Microbiol Rev. 2011 Jan;35(1):3-67 PMID: 20497229
  28. The QseC sensor kinase: a bacterial adrenergic receptor.
    Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10420-10425 PMID: 16803956
  29. The HMMTOP transmembrane topology prediction server.
    Bioinformatics. 2001 Sep;17(9):849-50 PMID: 11590105
  30. Sequence similarity between the channel-forming domains of voltage-gated ion channel proteins and the C-terminal domains of secondary carriers of the major facilitator superfamily.
    Microbiology (Reading). 2002 Dec;148(Pt 12):3760-2 PMID: 12480878
  31. Comparative genomics and functional analysis of the NiaP family uncover nicotinate transporters from bacteria, plants, and mammals.
    Funct Integr Genomics. 2012 Mar;12(1):25-34 PMID: 21953179
  32. Comparative genomic analysis of the hexuronate metabolism genes and their regulation in gammaproteobacteria.
    J Bacteriol. 2011 Aug;193(15):3956-63 PMID: 21622752
  33. Multidrug resistance proteins QacA and QacB from Staphylococcus aureus: membrane topology and identification of residues involved in substrate specificity.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3630-5 PMID: 8622987
  34. Bioinformatic analyses of transmembrane transport: novel software for deducing protein phylogeny, topology, and evolution.
    J Mol Microbiol Biotechnol. 2009;17(4):163-76 PMID: 19776645
  35. Modeling, docking, and simulation of the major facilitator superfamily.
    Biophys J. 2006 Nov 15;91(10):L84-6 PMID: 16980356
  36. Two domains of a dual-function NarK protein are required for nitrate uptake, the first step of denitrification in Paracoccus pantotrophus.
    Mol Microbiol. 2002 Apr;44(1):157-70 PMID: 11967076
  37. Transport capabilities of eleven gram-positive bacteria: comparative genomic analyses.
    Biochim Biophys Acta. 2007 Jun;1768(6):1342-66 PMID: 17490609
  38. Structural model for 12-helix transporters belonging to the major facilitator superfamily.
    J Bacteriol. 2003 Mar;185(5):1712-8 PMID: 12591890
  39. Tet(L) and tet(K) tetracycline-divalent metal/H+ antiporters: characterization of multiple catalytic modes and a mutagenesis approach to differences in their efflux substrate and coupling ion preferences.
    J Bacteriol. 2002 Sep;184(17):4722-32 PMID: 12169596
  40. A web-based program (WHAT) for the simultaneous prediction of hydropathy, amphipathicity, secondary structure and transmembrane topology for a single protein sequence.
    J Mol Microbiol Biotechnol. 2001 Oct;3(4):501-2 PMID: 11545267
  41. Transcriptional regulation of flhDC by QseBC and sigma (FliA) in enterohaemorrhagic Escherichia coli.
    Mol Microbiol. 2005 Sep;57(6):1734-49 PMID: 16135237
  42. Characterization of the protocatechuate 4,5-cleavage pathway operon in Comamonas sp. strain E6 and discovery of a novel pathway gene.
    Appl Environ Microbiol. 2010 Dec;76(24):8093-101 PMID: 20952641
  43. RegPrecise: a database of curated genomic inferences of transcriptional regulatory interactions in prokaryotes.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D111-8 PMID: 19884135
  44. Eukaryotic major facilitator superfamily transporter modeling based on the prokaryotic GlpT crystal structure.
    Mol Membr Biol. 2007 Sep-Dec;24(5-6):333-41 PMID: 17710637
  45. Major facilitator superfamily.
    Microbiol Mol Biol Rev. 1998 Mar;62(1):1-34 PMID: 9529885
  46. The nature and dynamics of bacterial genomes.
    Science. 2006 Mar 24;311(5768):1730-3 PMID: 16556833
  47. Genomics, genetics, and cell biology of magnetosome formation.
    Annu Rev Microbiol. 2009;63:501-21 PMID: 19575557
  48. Characterization of an Escherichia coli sulfite oxidase homologue reveals the role of a conserved active site cysteine in assembly and function.
    Biochemistry. 2005 Aug 2;44(30):10339-48 PMID: 16042411
  49. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
    Nucleic Acids Res. 1997 Sep 1;25(17):3389-402 PMID: 9254694
  50. Multidrug resistance: phylogenetic characterization of superfamilies of secondary carriers that include drug exporters.
    Methods Mol Biol. 2010;637:47-64 PMID: 20419429
  51. The Transporter Classification Database: recent advances.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D274-8 PMID: 19022853
  52. Computer-aided analyses of transport protein sequences: gleaning evidence concerning function, structure, biogenesis, and evolution.
    Microbiol Rev. 1994 Mar;58(1):71-93 PMID: 8177172
  53. Opening and closing of the periplasmic gate in lactose permease.
    Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3774-8 PMID: 18319336
  54. Two types of Bacillus subtilis tetA(L) deletion strains reveal the physiological importance of TetA(L) in K(+) acquisition as well as in Na(+), alkali, and tetracycline resistance.
    J Bacteriol. 2000 Apr;182(8):2088-95 PMID: 10735849
  55. Interdependence of two NarK domains in a fused nitrate/nitrite transporter.
    Mol Microbiol. 2008 Nov;70(3):667-81 PMID: 18823285
  56. The major facilitator superfamily.
    J Mol Microbiol Biotechnol. 1999 Nov;1(2):257-79 PMID: 10943556
  57. Rhomboid proteases and their biological functions.
    Annu Rev Genet. 2008;42:191-210 PMID: 18605900
  58. Proximity relationships between helices I and XI or XII in the lactose permease of Escherichia coli determined by site-directed thiol cross-linking.
    J Mol Biol. 1999 Aug 20;291(3):683-92 PMID: 10448046
  59. Basic local alignment search tool.
    J Mol Biol. 1990 Oct 5;215(3):403-10 PMID: 2231712
  60. Residues gating the periplasmic pathway of LacY.
    J Mol Biol. 2009 Nov 27;394(2):219-25 PMID: 19781551
Article Info
Journal
The FEBS journal
Abbr.
FEBS J
ISSN
1742-4658
DOI
10.1111/j.1742-4658.2012.08588.x
Published
2012-06-00
Epub
2012-00-08
Pages
2022-35
Language
English
Region
England
NLM ID
101229646
PMCID
PMC3425384
Subset
IM
Grants
NIGMS NIH HHS · R01 GM077402 · United States
NIGMS NIH HHS · 2 RO1 GM077402-05A1 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1111/j.1742-4658.2012.08588.x PMC Full Text View journal details
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