MOP flippase

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The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily (TC# 2.A.66) is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

  1. One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
  2. One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
  3. One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
  4. One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
  5. One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
  6. And finally, one (Ank) that shuttles inorganic pyrophosphate (PPi) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family

All functionally characterized members of the MOP superfamily catalyze efflux of their substrates, presumably by cation antiport.[1][2]

Functionally characterized families[edit]

2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family[edit]

Main article: Multi-antimicrobial extrusion protein
Multi-antimicrobial extrusion protein
Identifiers
SymbolMatE
PfamPF01554
Pfam clanCL0222
InterProIPR002528
TCDB2.A.66
OPM superfamily220
OPM protein3mkt
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The MATE family is made up of several members and includes a functionally characterized multidrug efflux system from Vibrio parahaemolyticus NorM (TC# 2.A.66.1.1), and several homologues from other closely related bacteria that function by a drug:Na+ antiport mechanism, a putative ethionine resistance protein of Saccharomyces cerevisiae (ERC1 (YHR032w); TC# 2.A.66.1.5), a cationic drug efflux pump in A. thaliana (i.e., AtDTX1 aka AT2G04040; TC# 2.A.66.1.8) and the functionally uncharacterized DNA damage-inducible protein F (DinF; TC# 2.A.66.1.4) of E. coli.[3]

The family includes hundreds of functionally uncharacterized but sequenced homologues from bacteria, archaea, and all eukaryotic kingdoms.[4] A representative list of proteins belonging to the MATE family can be found in the Transporter Classification Database.

Structure[edit]

The bacterial proteins are of about 450 amino acyl residues in length and exhibit 12 putative transmembrane segments (TMSs). They arose by an internal gene duplication event from a primordial 6 TMS encoding genetic element. The yeast proteins are larger (up to about 700 residues) and exhibit about 12 TMSs.

hMATE1[edit]

Human MATE1 (hMATE1) is an electroneutral H+/organic cation (OC) exchanger responsible for the final excretion step of structurally unrelated toxic organic cations in kidney and liver. Glu273, Glu278, Glu300 and Glu389 are conserved in the transmembrane regions. Substitution with alanine or aspartate reduced export of tetraethylammonium (TEA) and cimetidine, and several had altered substrate affinities.[5] Thus, all of these glutamate residues are involved in binding and/or transport of TEA and cimetidine, but their roles are different.

MATE (NorM) Transport Reaction[edit]

The probable transport reaction catalyzed by NorM, and possibly by other proteins of the MATE family is:

Antimicrobial (in) + nNa+ (out) → Antimicrobial (out) + nNa+ (in).

2.A.66.2 The Polysaccharide Transport (PST) Family[edit]

Analyses conducted in 1997 showed that members of the PST family formed two major clusters.[6] One is concerned with lipopolysaccharide O-antigen (undecaprenol pyrophosphate-linked O-antigen repeat unit) export (flipping from the cytoplasmic side to the periplasmic side of the inner membranes) in Gram-negative bacteria. On the periplasmic side, polymerization occurs catalyzed by Wzy.[7] The other is concerned with exopolysaccharide or capsular polysaccharide export in both Gram-negative and Gram-positive bacteria. However, archaeal and eukaryotic homologues are now recognized. The mechanism of energy coupling is not established, but homology with the MATE family suggests that they are secondary carriers. These transporters may function together with auxiliary proteins that allow passage across just the cytoplasmic membrane or both membranes of the Gram-negative bacterial envelope. They may also regulate transport. Thus, each Gram-negative bacterial PST system specific for an exo- or capsular polysaccharide functions in conjunction with a cytoplasmic membrane-periplasmic auxiliary (MPA) protein with a cytoplasmic ATP-binding domain (MPA1-C; TC# 3.C.3) as well as an outer membrane auxiliary protein (OMA; TC #3.C.5). Each Gram-positive bacterial PST system functions in conjunction with a homologous MPA1 + C pair of proteins equivalent to an MPA1-C proteins of Gram-negative bacteria. The C-domain has been shown to possess tyrosine protein kinase activity, so it may function in a regulatory capacity. The lipopolysaccharide exporters may function specifically in the translocation of the lipid-linked O-antigen side chain precursor from the inner leaflet of the cytoplasmic membrane to the outer leaflet.[8] In this respect, they correlate in function with the flippase activities of members of the oligosaccharidyl-lipid flippase (OLF) family of the MVF families.

Structure[edit]

The protein members of the PST family are generally of 400-500 amino acyl residues in length and traverse the membrane as putative α-helical spanners twelve times.

PST Transport Reaction[edit]

The generalized transport reaction catalyzed by PST family proteins is:

Lipid-linked polysaccharide precursor (in) + energy → Lipid-linked polysaccharide precursor (out).

2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family[edit]

The OLF family is found in the endoplasmic reticular membranes of eukaryotes. N-linked glycosylation in eukaryotic cells follows a conserved pathway in which a tetradecasaccharide substrate (Glc3Man9GlcNAc2) is initially assembled in the ER membrane as a dolichylpyrophosphate (Dol-PP)-linked intermediate before being transferred to an asparaginyl residue in a lumenal protein. An intermediate, Man5GlcNAc2-PP-Dol is made on the cytoplasmic side of the membrane and translocated across the membrane so that the oligosaccharide chain faces the ER lumen where biosynthesis continues to completion. The flippase that catalyzes the translocation step is dependent on the Rft1 protein (TC# 2.A.66.3.1) of S. cerevisiae.[9]

Homologues[edit]

Homologues are found in plants, animals and fungi including C. elegans, D. melanogaster, H. sapiens, A. thaliana, S. cerevisiae and S. pombe. These proteins are distantly related to MATE and PST family members and therefore are believed to be secondary carriers.

Structure[edit]

The yeast protein, called the nuclear division Rft1 protein (TC# 2.A.66.3.1), is 574 aas with 12 putative TMSs. The homologue in A. thaliana is 401 aas in length with 8 or 9 putative TMSs while that in C. elegans is 522 aas long with 11 putative TMSs.

2.A.66.4 The Mouse Virulence Factor (MVF) Family[edit]

One member of the MVF family, MviN (TC# 2.A.66.4.1) of Salmonella typhimurium, has been shown to be an important virulence factor for this organism when infecting the mouse.[10] In several bacteria, mviN genes occur in operons including glnD genes that encode the uridyl transferase that participates in the regulation of nitrogen metabolism.[11] It is thought that MviN may flip the Lipid II peptidoglycan (PG) precursor from the cytoplasmic side of the inner membrane to the periplasmic surface acting as a putative lipid flippase in Salmonella typhimurium.[12][13] In E. coli, MviN is an essential protein which when defective results in the accumulation of polyprenyl diphosphate-N-acetylmuramic acid-(pentapeptide)-N-acetyl-glucosamine, thought to be the peptidoglycan intermediated exported via MviN.[14] In Mycobacterium tuberculosis, MviN is thought to play an essential role in peptidoglycan biosynthesis.[15]

Another MVF protein, MurJ, functions as a peptidoglycan biosynthesis protein.[16] A 3-d structural model shows that MurJ contains a solvent-exposed cavity within the plane of the membrane.[17] MurJ has 14 TMSs, and specific charged residues localized in the central cavity are essential for function. This structural homology model suggests that MurJ functions as an essential transporter in PG biosynthesis.[17] Based on an in vivo assay, MurJ acts as a flippase for the lipid-linked cell wall precursor, polyisoprenoid-linked disaccharide-peptapeptide.[18] There is controversy about the role of this porter and FtsW/RodA which on the basis of an in vitro assay, were thought to be flippases for the same intermediate.[19]

2.A.66.5 The Agrocin 84 Antibiotic Exporter (AgnG) Family[edit]

Agrocin 84 is a disubstituted adenine nucleotide antibiotic made by and specific for Agrobacteria. It is encoded by the pAgK84 plasmid of A. tumefaciens [20] and targets a tRNA synthetase.[21] The agnG gene encodes a protein of 496 aas with 12-13 putative TMSs and a short hydrophilic N-terminal domain of 80 residues. A TCDB Blast search with 2 iterations shows that members of the AgnG family are related to the U-MOP12 family (TC# 2.A.66.12) and the PST family (TC# 2.A.66.2) and more distantly related to the OLF (TC# 2.A.66.3), MVF (TC# 2.A.66.4), and LPS-F (TC# 2.A.66.10) families.

Transport Reaction[edit]

The reaction catalyzed by AgnG is:

agrocin (in) → agrocin (out)

AgnG homologue 2 of Lyngbya sp. (TC# 2.A.66.5.3) is thought to be a polysaccharide exporter.[22]

2.A.66.9 The Progressive Ankylosis (Ank) Family[edit]

Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. An autosomal dominant form of the disorder has been linked to chromosome 5p15.2-p14.1 within a region harboring the human homolog (ANKH; TC# 2.A.66.9.1) of the mouse progressive ankylosis (ank) gene. The ANK protein spans the cell membrane and shuttles inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption.[23]

Structure[edit]

The ANK protein has 12 membrane-spanning helices with a central channel permitting the passage of PPi. Mutations occur at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. The PPi carrier ANK is concerned with bone formation and remodeling.[23]

Other Families[edit]

  • 2.A.66.6 - The Putative Exopolysaccharide Exporter (EPS-E) Family
  • 2.A.66.7 - Putative O-Unit Flippase (OUF) Family
  • 2.A.66.8 - Unknown MOP-1 (U-MOP1) Family
  • 2.A.66.10 - LPS Precursor Flippase (LPS-F) Family
  • 2.A.66.11 - Uncharacterized MOP-11 (U-MOP11) Family
  • 2.A.66.12 - Uncharacterized MOP-12 (U-MOP12) Family

See also[edit]

References[edit]

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  2. ^ Yen MR, Chen JS, Marquez JL, Sun EI, Saier MH (2010-01-01). "Multidrug Resistance: Phylogenetic Characterization of Superfamilies of Secondary Carriers that Include Drug Exporters". Membrane Transporters in Drug Discovery and Development. Methods in Molecular Biology. Vol. 637. pp. 47–64. doi:10.1007/978-1-60761-700-6_3. ISBN 978-1-60761-699-3. PMID 20419429.
  3. ^ Saier, MH Jr. "2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
  4. ^ Kuroda T, Tsuchiya T (May 2009). "Multidrug efflux transporters in the MATE family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1794 (5): 763–8. doi:10.1016/j.bbapap.2008.11.012. PMID 19100867.
  5. ^ Matsumoto T, Kanamoto T, Otsuka M, Omote H, Moriyama Y (April 2008). "Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter". American Journal of Physiology. Cell Physiology. 294 (4): C1074–8. doi:10.1152/ajpcell.00504.2007. PMID 18305230.
  6. ^ Paulsen IT, Beness AM, Saier MH (August 1997). "Computer-based analyses of the protein constituents of transport systems catalysing export of complex carbohydrates in bacteria". Microbiology. 143 ( Pt 8) (8): 2685–99. doi:10.1099/00221287-143-8-2685. PMID 9274022.
  7. ^ Marolda CL, Tatar LD, Alaimo C, Aebi M, Valvano MA (July 2006). "Interplay of the Wzx translocase and the corresponding polymerase and chain length regulator proteins in the translocation and periplasmic assembly of lipopolysaccharide o antigen". Journal of Bacteriology. 188 (14): 5124–35. doi:10.1128/JB.00461-06. PMC 1539953. PMID 16816184.
  8. ^ Islam ST, Lam JS (April 2013). "Wzx flippase-mediated membrane translocation of sugar polymer precursors in bacteria". Environmental Microbiology. 15 (4): 1001–15. doi:10.1111/j.1462-2920.2012.02890.x. PMID 23016929.
  9. ^ Helenius J, Ng DT, Marolda CL, Walter P, Valvano MA, Aebi M (January 2002). "Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein". Nature. 415 (6870): 447–50. doi:10.1038/415447a. PMID 11807558. S2CID 4419970.
  10. ^ Kutsukake K, Okada T, Yokoseki T, Iino T (May 1994). "Sequence analysis of the flgA gene and its adjacent region in Salmonella typhimurium, and identification of another flagellar gene, flgN". Gene. 143 (1): 49–54. doi:10.1016/0378-1119(94)90603-3. PMID 8200538.
  11. ^ Rudnick PA, Arcondéguy T, Kennedy CK, Kahn D (April 2001). "glnD and mviN are genes of an essential operon in Sinorhizobium meliloti". Journal of Bacteriology. 183 (8): 2682–5. doi:10.1128/JB.183.8.2682-2685.2001. PMC 95188. PMID 11274131.
  12. ^ Vasudevan P, McElligott J, Attkisson C, Betteken M, Popham DL (October 2009). "Homologues of the Bacillus subtilis SpoVB protein are involved in cell wall metabolism". Journal of Bacteriology. 191 (19): 6012–9. doi:10.1128/JB.00604-09. PMC 2747891. PMID 19648239.
  13. ^ Fay A, Dworkin J (October 2009). "Bacillus subtilis homologs of MviN (MurJ), the putative Escherichia coli lipid II flippase, are not essential for growth". Journal of Bacteriology. 191 (19): 6020–8. doi:10.1128/JB.00605-09. PMC 2747889. PMID 19666716.
  14. ^ Inoue A, Murata Y, Takahashi H, Tsuji N, Fujisaki S, Kato J (November 2008). "Involvement of an essential gene, mviN, in murein synthesis in Escherichia coli". Journal of Bacteriology. 190 (21): 7298–301. doi:10.1128/JB.00551-08. PMC 2580715. PMID 18708495.
  15. ^ Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T (January 2012). "A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria". Science Signaling. 5 (208): ra7. doi:10.1126/scisignal.2002525. PMC 3664666. PMID 22275220.
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  17. ^ a b Butler EK, Davis RM, Bari V, Nicholson PA, Ruiz N (October 2013). "Structure-function analysis of MurJ reveals a solvent-exposed cavity containing residues essential for peptidoglycan biogenesis in Escherichia coli". Journal of Bacteriology. 195 (20): 4639–49. doi:10.1128/JB.00731-13. PMC 3807429. PMID 23935042.
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  19. ^ Young KD (July 2014). "Microbiology. A flipping cell wall ferry". Science. 345 (6193): 139–40. doi:10.1126/science.1256585. PMID 25013047. S2CID 12072256.
  20. ^ Kim JG, Park BK, Kim SU, Choi D, Nahm BH, Moon JS, Reader JS, Farrand SK, Hwang I (June 2006). "Bases of biocontrol: sequence predicts synthesis and mode of action of agrocin 84, the Trojan horse antibiotic that controls crown gall". Proceedings of the National Academy of Sciences of the United States of America. 103 (23): 8846–51. Bibcode:2006PNAS..103.8846K. doi:10.1073/pnas.0602965103. PMC 1482666. PMID 16731618.
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  22. ^ "2.A.66.5: The Agrocin 84 Antibiotic Exporter (AgnG) Family". Transporter Classification Database. Retrieved 2016-03-08.
  23. ^ a b Nürnberg P, Thiele H, Chandler D, Höhne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N, Tinschert S (May 2001). "Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia". Nature Genetics. 28 (1): 37–41. doi:10.1038/88236. PMID 11326272.

As of 19:37, 24 February 2016 (UTC), this article is derived in whole or in part from Transporter Classification Database, authored by Saier Lab. The copyright holder has licensed the content in a manner that permits reuse under CC BY-SA 3.0 and GFDL. All relevant terms must be followed. The original text was at "2.A.66 The Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily"

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