Major Facilitator Superfamily
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The major facilitator superfamily (MFS) is a
superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
of
membrane transport protein A membrane transport protein (or simply transporter) 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 transmembran ...
s that facilitate movement of small
solutes In chemistry, a solution is a special type of homogeneous mixture composed of two or more substances. In such a mixture, a solute is a substance dissolved in another substance, known as a solvent. If the attractive forces between the solvent ...
across
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s in response to chemiosmotic gradients.


Function

The major facilitator superfamily (MFS) are membrane proteins which are expressed ubiquitously in all kingdoms of life for the import or export of target substrates. The MFS family was originally believed to function primarily in the uptake of sugars but subsequent studies revealed that drugs, metabolites,
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
s,
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
and
oxyanion An oxyanion, or oxoanion, is an ion with the generic formula (where A represents a chemical element and O represents an oxygen atom). Oxyanions are formed by a large majority of the chemical elements. The formulae of simple oxyanions are determine ...
s were all transported by MFS family members. These protein energetically drive transport utilizing the electrochemical gradient of the target substrate (
uniporter A uniporter is a membrane transport protein that transports a single species of substrate ( charged or uncharged) across a cell membrane. It may use either facilitated diffusion and transport along a diffusion gradient or transport against one ...
), or act as a
cotransporter Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They e ...
where transport is coupled to the movement of a second substrate.


Fold

The basic fold of the MFS transporter is built around 12, or in some cases, 14
transmembrane helices A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...
(TMH), with two 6- (or 7- ) helix bundles formed by the N and C terminal homologous domains of the transporter which are connected by an extended cytoplasmic loop. The two halves of the protein pack against each other in a clam-shell fashion, sealing via interactions at the ends of the transmembrane helices and extracellular loops. This forms a large aqueous cavity at the center of the membrane, which is alternatively open to the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
or
periplasm 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 ...
/extracellular space. Lining this aqueous cavity are the
amino-acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
which bind the substrates and define transporter specificity. Many MFS transporters are thought to be dimers through
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
methods, with some evidence to suggest a functional role for this
oligomerization In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
.


Mechanism

The alternating-access mechanism thought to underlie the transport of most MFS transport is classically described as the "rocker-switch" mechanism. In this model, the transporter opens to either the extracellular space or cytoplasm and simultaneously seals the opposing face of the transporter, preventing a continuous pathway across the membrane. For example, in the best studied MFS transporter, LacY,
lactose Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...
and
protons A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
typically bind from the periplasm to specific sites within the aqueous cleft. This drives closure of the extracellular face, and opening of the cytoplasmic side, allowing substrate into the cell. Upon substrate release, the transporter recycles to the periplasmic facing orientation. Exporters and antiporters of the MFS family follow a similar reaction cycle, though exporters bind substrate in the cytoplasm and extrude it to the extracellular or periplasmic space, while antiporters bind substrate in both states to drive each conformational change. While most MFS structures suggest large, rigid body structural changes with substrate binding, the movements may be small in the cases of small substrates, such as the nitrate transporter NarK.


Transport

The generalized transport reactions catalyzed by MFS porters are: # Uniport: S (out) ⇌ S (in) # Symport: S (out) + + or Na+(out) ⇌ S (in) + + or Na+(in) # Antiport: S1 (out) + S2 (in) ⇌ S1 (in) + S2 (out) (S1 may be H+ or a solute)


Substrate specificity

Though initially identified as sugar transporters, a function conserved from prokaryotes to mammals, the MFS family is notable for the great diversity of substrates transported by the superfamily. These range from small oxyanions to large peptide fragments. Other MFS transporters are notable for a lack of selectivity, extruding broad classes of drugs and xenobiotics. This substrate specificity is largely determined by specific side chains which line the aqueous pocket at the center of the membrane. While one substrate of particular biological importance is often used to name the transporter or family, there may also be co-transported or leaked ions or molecules. These include water molecules or the coupling ions which energetically drive transport.


Structures

The
crystal structures A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...
of a number of MFS transporters have been characterized. The first structures were of the
glycerol 3-phosphate ''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of three stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of glycerophospholipids. Equally appropriat ...
/
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phospho ...
exchanger GlpT and the
lactose Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...
-
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
symporter LacY, which served to elucidate the overall structure of the protein family and provided initial models for understanding the MFS transport mechanism. Since these initial structures other MFS structures have been solved which illustrate substrate specificity or states within the reaction cycle. While the initial MFS structures solved were of bacterial transporters, recently structures of the first
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
structures have been published. These include a fungal phosphate transporter PiPT, plant nitrate transporter NRT1.1, and the human
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
transporter
GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose across ...
.


Evolution

The origin of the basic MFS transporter fold is currently under heavy debate. All currently recognized MFS permeases have the two six-TMH domains within a single polypeptide chain, although in some MFS families an additional two TMHs are present. Evidence suggests that the MFS permeases arose by a tandem intragenic duplication event in the early prokaryotes. This event generated the 12 transmembrane helix topology from a (presumed) primordial 6-helix dimer. Moreover, the well-conserved MFS specific motif between TMS2 and TMS3 and the related but less well conserved motif between TMS8 and TMS9 prove to be a characteristic of virtually all of the more than 300 MFS proteins identified. However, the origin of the primordial 6-helix domain is under heavy debate. While some functional and structural evidence suggests that this domain arose out of a simpler 3-helix domain, bioinformatic or phylogenetic evidence supporting this hypothesis is lacking.


Medical significance

MFS family members are central to human physiology and play an important role in a number of diseases, through aberrant action, drug transport, or drug resistance. The OAT1 transporter transports a number of nucleoside analogs central to antiviral therapy. Resistance to antibiotics is frequently the result of action of MFS resistance genes. Mutations in MFS transporters have also been found to be cause neurodegerative disease, vascular disorders of the brain, and glucose storage diseases.


Disease mutations

Disease associated mutations have been found in a number of human MFS transporters; those annotated in
Uniprot UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains a large amount of information about the biological function of proteins derived from ...
are listed below.


Human MFS proteins

There are several MFS proteins in humans, where they are known as solute carriers (SLCs) and
Atypical SLCs Atypical Solute Carrier Families (Atypical SLCs) are novel plausible secondary active or facilitative transporter proteins that share ancestral background with the known solute carrier families (SLCs). However, they have not been assigned a name a ...
. There are today 52 SLC families, of which 16 families include MFS proteins; SLC2, 15 16, 17, 18, 19, SLCO (SLC21), 22, 29, 33, 37, 40, 43, 45, 46 and 49. Atypical SLCs are MFS proteins, sharing sequence similarities and evolutionary origin with SLCs, but they are not named according to the SLC root system, which originates from the hugo gene nomenclature system (HGNC). All atypical SLCs are listed in detail in, but they are: MFSD1,
MFSD2A Major facilitator superfamily domain-containing protein 2 (MFSD2 or MFSD2A) -- also known as sodium-dependent lysophosphatidylcholine symporter 1 -- is a protein that in humans is encoded by the ''MFSD2A'' gene. MFSD2A is a membrane transport pr ...
, MFSD2B,
MFSD3 Major facilitator superfamily domain containing 3 (MFSD3) is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organ ...
, MFSD4A, MFSD4B, MFSD5, MFSD6, MFSD6L, MFSD8,
MFSD9 Major facilitator superfamily domain-containing protein 9 is a protein that in humans is encoded by the MFSD9 gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity. ...
, MFSD10,
MFSD11 Major facilitator superfamily The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients. Function The major fac ...
,
MFSD12 Major facilitator superfamily domain containing 1 (MFSD1, SMAP) is a protein belonging to the MFS Pfam clan. It is an Atypical solute carrier. It belongs to the major facilitator superfamily MFS Pfam Clan. MFSD1 has been identified in neuronal pl ...
, MFSD13A, MFSD14A,
MFSD14B Major facilitator superfamily The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients. Function The major fac ...
,
UNC93A Unc-93 homolog A (C. elegans) is a protein that in humans is encoded by the UNC93A gene. Unc93A is a major facilitator superfamily (MFS), and a putative solute carrier in humans. It belongs to the atypical SLCs that was recently listed. It is th ...
,
UNC93B1 Unc-93 homolog B1 (''C. elegans''), also known as UNC93B1, is a protein which in humans is encoded by the ''UNC93B1'' gene. Function This gene encodes a protein with similarity to the ''Caenorhabditis elegans'' unc93 protein. The Unc93 protein ...
, SV2A, SV2B, SV2C, SVOP, SVOPL, SPNS1, SPNS2, SPNS3 and
CLN3 G1/S-specific cyclin Cln3 is a protein that is encoded by the ''CLN3'' gene. The Cln3 protein is a budding yeast G1 cyclin that controls the timing of ''Start'', the point of commitment to a mitotic cell cycle. It is an upstream regulator of t ...
. As there is high sequence identity and phylogenetic resemblance between the atypical SLCs of MFS type, they can be divided into 15 AMTFs (Atypical MFS Transporter Families), suggesting there are at least 64 different families including SLC proteins of MFS type.


References

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