Tripartite ATP-independent periplasmic transporter

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DctP component of Tripartite ATP-independent periplasmic transporter
Identifiers
SymbolDctP
Pfam PF03480
Pfam clan CL0177
InterPro IPR018389
TCDB 2.A.56
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
DctQ component of Tripartite ATP-independent periplasmic transporter
Identifiers
SymbolDctQ
Pfam PF04290
InterPro IPR007387
TCDB 2.A.56
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
DctM-like transporters
Identifiers
SymbolDctM
Pfam PF06808
Pfam clan CL0182
InterPro IPR010656
TCDB 2.A.56
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Tripartite ATP-independent periplasmic transporters (TRAP transporters) are a large family of solute transporters found in bacteria and archaea, but not in eukaryotes, that appear to be specific for the uptake of organic acids or related molecules containing a carboxylate or sulfonate group. They are unique in that they utilize a substrate binding protein (SBP) in combination with a secondary transporter.

Contents

History

A schematic illustrating the key features of a TRAP transporter in comparison to an ABC transporter and a classical secondary transporter. TRAPcomparison.jpg
A schematic illustrating the key features of a TRAP transporter in comparison to an ABC transporter and a classical secondary transporter.

TRAP transporters were discovered in the laboratory of Prof. David J. Kelly at the University of Sheffield, UK. His group were working on the mechanism used by the photosynthetic bacterium Rhodobacter capsulatus to take up certain dicarboxylic acids. They characterised a binding protein component (DctP) of a transporter that recognized these compounds, which they assumed would form part of a typical ABC transporter, but when they sequenced the genes surrounding dctP they found two other genes encoding integral membrane proteins, dctQ and dctM, but no genes encoding components of an ABC transporter. [1] They further showed that uptake of the same dicarboxylates was independent of ATP and that uptake required an electrochemical ion gradient, making this a unique binding protein-dependent secondary transporter. [1]

Since these early studies, it has become clear that TRAP transporters are present in many bacteria and archaea, [2] with many bacterial having multiple TRAP transporters, some having over 20 different systems. [3]

Substrates

To date, most substrates for TRAP transporters contain a common feature which is that they are organic acids. [4] This includes C4-dicarboxylates such as succinate, malate and fumarate, [1] keto-acids such as pyruvate and alpha-ketobutyrate [5] [6] and the sugar acid, N-acetyl neuraminic acid (or sialic acid). [7] Other substrates include the compatible solute ectoine and hydroxyectoine and pyroglutamate. [4]

Composition

All known TRAP transporters contain 3 protein domains. These are the solute binding protein (the SBP), the small membrane protein domain and the large membrane protein domain. Following the nomenclature for the first characterized TRAP transporter, DctPQM, these subunits are usually named P, Q and M respectively. [4] Around 10% of TRAP transporters have natural genetic fusions between the two membrane protein components, and in the one well studied example of this in the sialic acid specific TRAP transporter from Haemophilus influenzae the fused gene has been named siaQM.

Mechanism

By using an SBP, TRAP transporters share some similarity to ABC transporters in that the substrate for the transporter is initially recognized outside of the cytoplasmic membrane. In Gram-negative bacteria, the SBP is usually free in the periplasm and expressed at relatively high levels compared to the membrane domains. [1] In Gram positive bacteria and archaea, the SBP is tethered to the cytoplasmic membrane. In both types of systems the SBP binds to substrate, usually with low micromolar affinity, [4] which causes a significant conformation change in the protein, akin to a Venus flytrap closing. The trapped substrate is then delivered to the membrane domains of the transporter, where the electrochemical ion gradient is somehow exploited to open the SBP, extract the substrate and catalyse its movement across the membrane. For the SiaPQM TRAP transporter which has been studied in a fully reconstituted in vitro form, uptake uses a Na+
 gradient and not proton gradient to drive uptake. [8] The SiaPQM systems also exhibits unique properties for a secondary transporter in that it cannot catalyse bidirectional transport as the SBP imposes that movement is only in the direction of uptake into the cell. [8]

Structure

Substrate binding protein (SBP)

Following the first structure of a TRAP SBP in 2005, [9] there are now over 10 different structures available. [10] [11] [12] They all have very similar overall structures, with two globular domains linked by a hinge. The substrate binding site is formed by both the domains which enclose the substrate. A highly conserved arginine residue in the TRAP SBPs forms a salt bridge with a carboxylate group on the substrate, which is important for substrate recognition. [10]

Membrane subunits

The first structure of the membrane domains was solved for the sialic acid transporter from Haemophilus influenzae. [13] [14] Confirmed by another TRAP transporter structure, [15] the structures reveal a monomeric elevator-like transport mechanism for TRAP transporter. While the larger M-subunit forms the stator- and elevator-domain, the Q-subunit seems to enlarge and stabilize the stator-domain of the monomeric transporter. Current models suggest a binding of the SBP with both functional parts of the transporter, the stator- and elevator domain, and show a matched conformational coupling between the inward-open and outward-open state of the membrane subunits to the opened and closed state of the SBP. [13] [14]

Related Research Articles

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in gram-positive bacteria, between cell wall and the plasma membrane. The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">ATP-binding cassette transporter</span> Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

<span class="mw-page-title-main">Efflux (microbiology)</span> Protein complexes that move compounds, generally toxic, out of bacterial cells

In microbiology, efflux is the moving of a variety of different compounds out of cells, such as antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters. All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that encode efflux pumps. Efflux pumps actively move substances out of a microorganism, in a process known as active efflux, which is a vital part of xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.

The galactose permease or GalP found in Escherichia coli is an integral membrane protein involved in the transport of monosaccharides, primarily hexoses, for utilization by E. coli in glycolysis and other metabolic and catabolic pathways (3,4). It is a member of the Major Facilitator Super Family (MFS) and is homologue of the human GLUT1 transporter (4). Below you will find descriptions of the structure, specificity, effects on homeostasis, expression, and regulation of GalP along with examples of several of its homologues.

<i>N</i>-Acetylneuraminic acid Chemical compound

N-Acetylneuraminic acid is the predominant sialic acid found in human cells, and many mammalian cells. Other forms, such as N-Glycolylneuraminic acid, may also occur in cells.

<span class="mw-page-title-main">Mitochondrial carrier</span>

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.

Translocase is a general term for a protein that assists in moving another molecule, usually across a cell membrane. These enzymes catalyze the movement of ions or molecules across membranes or their separation within membranes. The reaction is designated as a transfer from “side 1” to “side 2” because the designations “in” and “out”, which had previously been used, can be ambiguous. Translocases are the most common secretion system in Gram positive bacteria.

In enzymology, an iron-chelate-transporting ATPase (EC 3.6.3.34) is an enzyme that catalyzes the chemical reaction

In enzymology, a vitamin B12-transporting ATPase (EC 3.6.3.33) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">CMP-sialic acid transporter</span> Protein-coding gene in the species Homo sapiens

CMP-sialic acid transporter is a protein that in humans is encoded by the SLC35A1 gene.

<span class="mw-page-title-main">Sodium-solute symporter</span> Group of transport proteins

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.

ABCdb is a biological database for the adenosine triphosphate-binding cassette (ABC) transporters encoded by completely sequenced archaeal and bacterial genomes. These proteins are important for transporting substances into cells and are found in all living organisms.

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

The Nicotinamide Ribonucleoside (NR) Uptake Permease (PnuC) Family is a family of transmembrane transporters that is part of the TOG superfamily. Close PnuC homologues are found in a wide range of Gram-negative and Gram-positive bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">ZnuABC</span> Class of transport proteins

ZnuABC is a high-affinity transporter specialized for transporting zinc ions as part of a system for metal ion homeostasis in bacteria. The complex is a member of the ATP-binding cassette (ABC) transporter protein family. The transporter contains three protein components:

Divalent anion:Na+ symporters were found in bacteria, archaea, plant chloroplasts and animals.

Arsenite resistance (Ars) efflux pumps of bacteria may consist of two proteins, ArsB and ArsA, or of one protein. ArsA proteins have two ATP binding domains and probably arose by a tandem gene duplication event. ArsB proteins all possess twelve transmembrane spanners and may also have arisen by a tandem gene duplication event. Structurally, the Ars pumps resemble ABC-type efflux pumps, but there is no significant sequence similarity between the Ars and ABC pumps. When only ArsB is present, the system operates by a pmf-dependent mechanism, and consequently belongs in TC subclass 2.A. When ArsA is also present, ATP hydrolysis drives efflux, and consequently the system belongs in TC subclass 3.A. ArsB therefore appears twice in the TC system but ArsA appears only once. These pumps actively expel both arsenite and antimonite.

<span class="mw-page-title-main">Resistance-nodulation-cell division superfamily</span>

Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND superfamily includes seven families: the heavy metal efflux (HME), the hydrophobe/amphiphile efflux-1, the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the eukaryotic sterol homeostasis family, and the hydrophobe/amphiphile efflux-3 family. These RND systems are involved in maintaining homeostasis of the cell, removal of toxic compounds, and export of virulence determinants. They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant bacterial infections were reported in the 1940s after the first mass production of antibiotics. Most of the RND superfamily transport systems are made of large polypeptide chains. RND proteins exist primarily in gram-negative bacteria but can also be found in gram-positive bacteria, archaea, and eukaryotes.

References

  1. 1 2 3 4 Forward J.A.; Behrendt M.C.; Wyborn N.R.; Cross R.; Kelly D.J. (1997). "TRAP transporters: a new family of periplasmic solute transport systems encoded by the dctPQM genes of Rhodobacter capsulatus and by homologs in diverse gram-negative bacteria". J. Bacteriol. 179 (17): 5482–5493. doi:10.1128/jb.179.17.5482-5493.1997. PMC   179420 . PMID   9287004.
  2. ↑ Rabus R.; Jack D.L.; Kelly D.J.; Saier M.H. Jr. (1999). "TRAP transporters: an ancient family of extracytoplasmic solute-receptor-dependent secondary active transporters". Microbiology. 145 (12): 3431–3445. doi: 10.1099/00221287-145-12-3431 . PMID   10627041.
  3. ↑ Mulligan C.; Kelly D.J.; Thomas G.H. (2007). "Tripartite ATP-independent periplasmic transporters: application of a relational database for genome-wide analysis of transporter gene frequency and organization". J. Mol. Microbiol. Biotechnol. 12 (3–4): 218–226. doi:10.1159/000099643. PMID   17587870. S2CID   30920843.
  4. 1 2 3 4 Mulligan C.; Fischer M.; Thomas G. (2010). "Tripartite ATP-independent periplasmic (TRAP) transporters in bacteria and archaea". FEMS Microbiol. Rev. 35 (1): 68–86. doi: 10.1111/j.1574-6976.2010.00236.x . PMID   20584082.
  5. ↑ Thomas GH, Southworth T, León-Kempis MR, Leech A, Kelly DJ (2006). "Novel ligands for the extracellular solute receptors of two bacterial TRAP transporters". Microbiology. 152 (2): 187–198. doi: 10.1099/mic.0.28334-0 . PMID   16385129.
  6. ↑ Pernil R, Herrero A, Flores E (2010). "A TRAP transporter for pyruvate and other monocarboxylate 2-oxoacids in the cyanobacterium Anabaena sp. strain PCC 7120". J. Bacteriol. 192 (22): 6089–6092. doi:10.1128/JB.00982-10. PMC   2976462 . PMID   20851902.
  7. ↑ Severi E, Randle G, Kivlin P, Whitfield K, Young R, Moxon R, Kelly D, Hood D, Thomas GH (2005). "Sialic acid transport in Haemophilus influenzae is essential for lipopolysaccharide sialylation and serum resistance and is dependent on a novel tripartite ATP-independent periplasmic transporter". Mol. Microbiol. 58 (4): 1173–1185. doi: 10.1111/j.1365-2958.2005.04901.x . PMID   16262798. S2CID   32085592.
  8. 1 2 Mulligan C.; Geertsma E.R.; Severi E.; Kelly D.J.; Poolman B.; Thomas G.H. (2009). "The substrate-binding protein imposes directionality on an electrochemical sodium gradient-driven TRAP transporter". Proc. Natl. Acad. Sci. USA. 106 (6): 1778–1783. Bibcode:2009PNAS..106.1778M. doi: 10.1073/pnas.0809979106 . PMC   2644114 . PMID   19179287.
  9. ↑ Müller A.; Severi E.; Mulligan C.; Watts A.G.; Kelly D.J.; Wilson K.S.; Wilkinson A.J.; Thomas G.H. (2006). "Conservation of structure and mechanism in primary and secondary transporters exemplified by SiaP, a sialic acid binding virulence factor from Haemophilus influenzae" (PDF). J. Biol. Chem. 281 (31): 22212–22222. doi: 10.1074/jbc.M603463200 . PMID   16702222. S2CID   37483123.
  10. 1 2 Johnston J.W.; Coussens N.P.; Allen S.; Houtman J.C.; Turner K.H.; Zaleski A.; Ramaswamy S.; Gibson B.W.; Apicella M.A. (2008). "Characterization of the N-acetyl-5-neuraminic acid-binding site of the extracytoplasmic solute receptor (SiaP) of nontypeable Haemophilus influenzae strain 2019". J. Biol. Chem. 283 (2): 855–865. doi: 10.1074/jbc.M706603200 . PMID   17947229.
  11. ↑ Gonin S.; Arnoux P.; Pierru B.; Lavergne J.; Alonso B.; Sabaty M.; Pignol D. (2007). "Crystal structures of an Extracytoplasmic Solute Receptor from a TRAP transporter in its open and closed forms reveal a helix-swapped dimer requiring a cation for alpha-keto acid binding". BMC Struct. Biol. 7: 11. doi: 10.1186/1472-6807-7-11 . PMC   1839085 . PMID   17362499.
  12. ↑ Fischer M, Zhang QY, Hubbard RE, Thomas GH (2010). "Caught in a TRAP: substrate-binding proteins in secondary transport". Trends Microbiol. 18 (10): 471–478. doi:10.1016/j.tim.2010.06.009. PMID   20656493.
  13. 1 2 Hagelueken, Gregor; Peter, Martin F. (3 December 2021). "The structure of HiSiaQM defines the architecture of tripartite ATP-independent periplasmic (TRAP) transporters". bioRxiv. doi:10.1101/2021.12.03.471092. S2CID   244903475.
  14. 1 2 Peter, Martin F.; Hagelueken, Gregor (December 2022). "Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter". Nature Communications. 13 (1): 4471. Bibcode:2022NatCo..13.4471P. doi:10.1038/s41467-022-31907-y. PMC   9352664 . PMID   35927235.
  15. ↑ Renwick C.J. Dobson, James S. Davies (14 February 2022). "Structure and mechanism of the tripartite ATP-independent periplasmic (TRAP) transporter". bioRxiv. doi:10.1101/2022.02.13.480285. S2CID   246885457.
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