Snf3

High-affinity glucose transporter SNF3
Identifiers
Symbol	SNF3
RefSeq	NP_010087.1
UniProt	P10870

Last updated February 22, 2019

Snf3 is a protein which regulates glucose uptake in yeast. It senses glucose in the environment with high affinity.

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by human genome. GLUT is a type of uniporter transporter protein.

Introduction

Glucose sensing and signaling in budding yeast is similar to the mammalian system in many ways. However, there are also significant differences. Mammalian cells regulate their glucose uptake via hormones (i.e. insulin and glucagon) or intermediary metabolites. In contrast, yeast as a unicellular organism does not depend on hormones but on nutrients in the medium. The presence of glucose induces a conformational change in the membrane proteins Snf3/Rgt2 or Gpr1, and regulates expression of genes involved in glucose metabolism.

Saccharomyces cerevisiae is a species of yeast. It has been instrumental to winemaking, baking, and brewing since ancient times. It is believed to have been originally isolated from the skin of grapes. It is one of the most intensively studied eukaryotic model organisms in molecular and cell biology, much like Escherichia coli as the model bacterium. It is the microorganism behind the most common type of fermentation. S. cerevisiae cells are round to ovoid, 5–10 μm in diameter. It reproduces by a division process known as budding.

Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion and secondary active transport. Active transport is the movement of ions or molecules going against the concentration gradient.

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of carbohydrates, especially glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

Homology and function

Snf3 is homologous to multiple sugar transporters, it shares high similarity to the glucose transporters of rat brain cells and human HepG2 hepatoma cells, as well as to the arabinose and xylose transporters (AraE and XylE) of Escherichia coli .^[1] Based on this homology and on genetic studies, Snf3 was initially thought to be a high affinity glucose transporter.

In biology, homology is the existence of shared ancestry between a pair of structures, or genes, in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats, the arms of primates, the front flippers of whales and the forelegs of dogs and horses are all derived from the same ancestral tetrapod structure. Evolutionary biology explains homologous structures adapted to different purposes as the result of descent with modification from a common ancestor. The term was first applied to biology in a non-evolutionary context by the anatomist Richard Owen in 1843. Homology was later explained by Charles Darwin's theory of evolution in 1859, but had been observed before this, from Aristotle onwards, and it was explicitly analysed by Pierre Belon in 1555.

Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group.

Xylose is a sugar first isolated from wood, and named for it. Xylose is classified as a monosaccharide of the aldopentose type, which means that it contains five carbon atoms and includes an aldehyde functional group. It is derived from hemicellulose, one of the main constituents of biomass. Like most sugars, it can adopt several structures depending on conditions. With its free aldehyde group, it is a reducing sugar.

Later, it was found that Snf3 is not a glucose transporter, but rather a high affinity glucose sensor. It senses glucose at low concentrations and regulates transcription of the HXT genes, which encode for glucose transporters. If glucose is absent Snf3 is quiescent and transcription of the HXT genes is inhibited by a repressing complex. The complex consisting of several subunits such as Rgt1, Mth1/Std1, Cyc8 and Tup1 binds to the promoters of the HXT genes, thereby blocking their transcription.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

Snf3 is able to bind even low amounts of glucose due to its high affinity. The induction of Snf3 by glucose leads to the activation of YckI, a yeast casein kinase. This is followed by the recruitment of Mth1 and Std1 to the C-terminus of Snf3 which facilitates the phosphorylation of the two proteins by YckI. Phosphorylated Mth1 and Std1 are subsequently tagged for proteasome dependent degradation by SCF^Grrl, an E3 ubiquitin ligase. Therefore, the inhibitory complex misses two of its key components and cannot be assembled. Thus, repression of the HXT genes is abolished, leading to the expression of the glucose transporters and subsequently glucose import.^[2]

Casein pronounced "kay-seen" in British English, is a family of related phosphoproteins. These proteins are commonly found in mammalian milk, comprising c. 80% of the proteins in cow's milk and between 20% and 45% of the proteins in human milk.The j Casein has a wide variety of uses, from being a major component of cheese, to use as a food additive. The most common form of casein is sodium caseinate.

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the substrate gains a phosphate group and the high-energy ATP molecule donates a phosphate group. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis. Kinases are part of the larger family of phosphotransferases. Kinases should not be confused with phosphorylases, which catalyze the addition of inorganic phosphate groups to an acceptor, nor with phosphatases, which remove phosphate groups. The phosphorylation state of a molecule, whether it be a protein, lipid, or carbohydrate, can affect its activity, reactivity, and its ability to bind other molecules. Therefore, kinases are critical in metabolism, cell signalling, protein regulation, cellular transport, secretory processes, and many other cellular pathways, which makes them very important to human physiology.

The C-terminus is the end of an amino acid chain, terminated by a free carboxyl group (-COOH). When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. The convention for writing peptide sequences is to put the C-terminal end on the right and write the sequence from N- to C-terminus.

Structure

The putative topology of yeast Snf3. The C-terminal extension is not shown in its complete size. In reality it comprises 303 of the 845 residues. Topology.PNG — The putative topology of yeast Snf3. The C-terminal extension is not shown in its complete size. In reality it comprises 303 of the 845 residues.

Snf3 is a plasma membrane protein in yeasts that consists of 12 (2x6) transmembrane domains, like the homologous glucose transporters. Its structure is distinct from the homologous transporters in particular by a long C-terminal tail which is predicted to reside in the cytoplasm.

Membrane proteins are proteins that interact with, or are part of, biological membranes. They include integral membrane proteins that are permanently anchored or part of the membrane and peripheral membrane proteins that are only temporarily attached to the lipid bilayer or to other integral proteins. The integral membrane proteins are classified as transmembrane proteins that span across the membrane and integral monotopic proteins that are attached to only one side of the membrane. Membrane proteins are a common type of proteins along with soluble globular proteins, fibrous proteins, and disordered proteins. They are targets of over 50% of all modern medicinal drugs. It is estimated that 20–30% of all genes in most genomes encode membrane proteins.

Transmembrane domain usually denotes a transmembrane segment of single alpha helix of a transmembrane protein. More broadly, a transmembrane domain is any membrane-spanning protein domain.

In cell biology, the cytoplasm is all of the material within a 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 main components of the cytoplasm are cytosol – a gel-like substance, the organelles – the cell's internal sub-structures, and various cytoplasmic inclusions. The cytoplasm is about 80% water and usually colorless.

The long C-terminal tail plays an important role in glucose signaling and is probably the signaling domain itself. A soluble version of the C-terminal tail alone is sufficient to induce glucose transport.^[1]^[2]^[3]

All glucose transporters including Snf3 contain an arginine residue situated in a cytoplasmic loop preceding the fifth transmembrane domain. If this position is mutated, Snf3 adopts a state of constant glucose induction irrespective of whether there are nutrients present or not; this suggests an involvement in the glucose sensing process.

Regulation

The regulation of Snf3 in S. cerevisiae and its downstream events are still poorly understood, but it seems clear that a second glucose sensor Rgt2 influences Snf3 and vice versa. Furthermore, it is unclear whether these two proteins sense the glucose concentration on the outside or inside the cell. Snf3 and Rgt2 influence directly or indirectly several Hxt-transporters which are responsible for the glucose uptake. Low extracellular glucose concentrations are sensed by the Snf3 protein which probably leads to the expression of Hxt2-Genes for high affinity glucose transporters, while Rgt2 senses high glucose concentrations and leads to the expression of low affinity glucose transporters, like Hxt1 Although the downstream pathway is poorly understood it seems that Snf3 and Rgt2 transmit a signal directly or indirectly to Grr1, the DNA binding protein Rgt1, and the two cofactors Ssn6 and Tup1. Also needed for the transcription are the two nuclear proteins Mth1 and Std1.^[4]

Related Research Articles

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References

1 2 Celenza JL, Marshall-Carlson L, Carlson M (1988). The yeast SNF3 gene encodes a glucose transporter homologous to the mammalian protein. PNAS 85, 2130-2134
1 2 Rolland F, Winderickx J, Thevelein JM. (2002). Glucose-sensing and -signaling mechanisms in yeast. FEMS Yeast Res. 2, 183-201
↑ Marshall-Carlson L, Celenza JL, Laurent BC, Carlson M (1990). Mutational analysis of the SNF3 Glucose Transporter of Saccharomyces cerevisiae. Mol Cell Biol 10(3), 1105-1115
↑ Schneper L, Düvel K, Broach JR (2004). Sense and sensibility: nutritional response and signal integration in yeast. Current Opinion in Microbiology 7, 624-630

Gancedo MJ (2008). The early steps of glucose signaling in yeast. FEMS Microbiol Rev 32, 673-704
Kruckeberg AL, Walsh MC, Van Dam K (1998). How do yeast cells sense glucose? BioEssays 20, 972-976
Schneper L, Düvel K, Broach JR (2004). Sense and sensibility: nutritional response and signal integration in yeast. Current Opinion in Microbiology 7, 624-630

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[Celenza1988-1] 1 2 Celenza JL, Marshall-Carlson L, Carlson M (1988). The yeast SNF3 gene encodes a glucose transporter homologous to the mammalian protein. PNAS 85, 2130-2134

[Rolland2002-2] 1 2 Rolland F, Winderickx J, Thevelein JM. (2002). Glucose-sensing and -signaling mechanisms in yeast. FEMS Yeast Res. 2, 183-201

[Marshall1990-3] Marshall-Carlson L, Celenza JL, Laurent BC, Carlson M (1990). Mutational analysis of the SNF3 Glucose Transporter of Saccharomyces cerevisiae. Mol Cell Biol 10(3), 1105-1115

[Schneper2004-4] Schneper L, Düvel K, Broach JR (2004). Sense and sensibility: nutritional response and signal integration in yeast. Current Opinion in Microbiology 7, 624-630