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

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 A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...

(i.e.

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

and

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

) 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 biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

in the membrane proteins Snf3/Rgt2 or Gpr1, and regulates expression of genes involved in glucose metabolism.

Homology and function

Snf3 is

homologous Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor *Sequence homology, biological homology between DNA, RNA, or protein sequences * Homologous chrom ...

to multiple sugar transporters, it shares high similarity to the glucose transporters of rat brain cells and human

HepG2 Hep G2 (or HepG2) is a human liver cancer cell line. Hep G2 is an immortal cell line which was derived in 1975 from the liver tissue of a 15-year-old Caucasian male from Argentina with a well-differentiated hepatocellular carcinoma. T ...

hepatoma cells, as well as to the

arabinose Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group. For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, or structurally ...

and xylose transporters (AraE and XylE) of '' Escherichia coli''.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 Based on this homology and on genetic studies, Snf3 was initially thought to be a high affinity glucose transporter. 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. 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 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 high-energy ATP molecule don ...

. This is followed by the recruitment of Mth1 and Std1 to the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

of Snf3 which facilitates the

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of the two proteins by YckI. Phosphorylated Mth1 and Std1 are subsequently tagged for

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

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

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. 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. 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.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 All glucose transporters including Snf3 contain an

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

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

References

:* 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 {{Glucose metabolism Proteins Metabolism Receptors Membrane proteins