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(UDP)-glucose:glycoprotein glucosyltransferase or UGGT is a soluble, endoplasmic reticulum (ER) luminal protein found only in eukaryotes. UGGT is a glucosyltransferase, it catalyzes the transfer of a glucose molecule from a nucleotide sugar to an acceptor molecule. Uridine diphosphate glucose acts as a glucose donor for UGGT. UGGT is approximately 170 kDa and consists of three N-terminal thioredoxin (Trx)-like domains, a central β-domain, and a C-terminal catalytic domain.

UGGT is a part of the ER protein folding and quality control system that works to restore the normal folding processes of misfolded proteins. A protein is first recognized by UGGT and then glucosylated, allowing it to rebind to the lectin chaperone. The entire process allows proteins to evade degradation by endoplasmic reticulum associated degradation (ERAD) through re-glucosylation and the promotion of calnexin/calreticulin association.

History
In 1989, Trombetta and colleagues demonstrated that microsomal extracts glucosylated isolated thyroglobulin. This was the first evidence of ER reglucosylation activity. Their results showed that reglucosylation activity from ER extracts preferentially modified denatured thyroglobulin, as opposed to the native proteins. This ER reglucosylation activity was attributed to UGGT.

2.1 UGGT Encoding Gene
Genes encoding UGGT have been identified in organisms including C. elegans, Drosophila, S. pombe, rats, and humans. These genes produce polypeptides of approximately 1500 amino acid residues, with strong sequence homology.

2.2 Domains
A full crystal structure of UGGT has yet to be solved, however certain domains have been identified. UGGT is built of three N-terminal Trx-like domains, a central β-domain, and a C-terminal catalytic domain. A crystal structure of the third Trx domain has been obtained. The third Trx domain has a large hydrophobic patch shielded by the domain’s dynamic C-terminal helix.

The N-terminal sequence of UGGT is quite variable. UGGTs of different organisms display much lower N-terminal sequence homology than C-terminal homology.

The C-terminal catalytic domain is the most highly conserved portion of UGGT. Human UGGT displays 31-45% homology with Drosophila, C. elegans, and S. pombe UGGTs. The C-terminal domains display the highest degree of homology. The Leu1231, Arg1306, Arg1384, and Tyr1436 residues are conserved in the catalytic domain of most known UGGTs. UGGT has a C-terminal KDEL-type ER retention sequence, which ensures it is retained in the ER. An N-terminal 18 amino acid signal peptide allows UGGT to be translated by an ER tethered ribosome.

2.3 Isoforms
Humans and C. elegans produce two isoforms of UGGT: UGGT1 and UGGT2. UGGT1 and UGGT2 are encoded by separate genes. Human UGGT1 and UGGT2 share 50% sequence homology. Both human UGGT isoforms have been shown to have glucosyltransferase activity. Both C. elegans isoforms (CeUGGT1 and CeUGGT 2) have been shown to be enzymatically active, however only CeUGGT1 has been shown to display glucosyltransferase activity.

3.1 Recognition
UGGT is essential in the protein folding process, as it is the only protein element of the ER protein quality control system that can sense glycoprotein conformational states. UGGT senses the innermost GlcNAc moiety covalently linked to a misfolded glycoprotein. UGGT also recognizes exposed hydrophobic patches on proteins, a characteristic feature of misfolding. It is believed that the hydrophobic patch on the third Trx-like domain of UGGT may facilitate this recognition. Additionally, in proteins with multiple independently folding domains, UGGT recognizes folding defects at the level of individual domains. Consequently, reglucosylation occurs only in the misfolded domain.

3.2 Reglucosylation
When a nascent polypeptide enters the ER, a core glycan, Glc3Man9GlcNAc2, is transferred to the asparagine residues of any N-linked glycosylation consensus sequences present in the folding peptide. This glycan is then trimmed by the sequential actions of glucosidase I and II, into its monoglucosylated glycoform. This form is recognized by calnexin or calreticulin. UGGT functions to reglucosylate proteins which fail to fold, thus returning them to their monoglucosylated glycoform. When UGGT has recognized a misfolded protein it transfers a glucose monomer to the terminal mannose residue of the glycoprotein. Once the glucose monomer is bound the resident lectins, calnexin or calreticulin, retain the monoglucosylated glycoprotein in the ER. This trapping of proteins in their monoglucosylated state delays their secretion to the Golgi apparatus. Glucose units added to proteins by UGGT will be removed by Glucosidase II (GII). This removal causes the release of the glycoprotein from the lectin anchors.

Human UGGT has been shown to act with manganese and calcium ions as cofactors. Human UGGT has also been shown to complex with 15 kDa selenoprotein (Sep15). The formation of this heterodimer markedly increases the glucosyltransferase activity of UGGT.

Protein Trafficking Diseases
Many human diseases (cystic fibrosis, LPL deficiency), fall under the category of protein trafficking diseases. A dysfunctional element of the ERAD system can lead to the accumulation of mutant secretory proteins in the ER. This accumulation can cause a variety of diseases. Protein trafficking diseases have been divided into 3 groups:

1.	Diseases caused by the loss of coupling to the ER export machinery, leading to the immediate degradation of misfolded proteins (no refolding events with UGGT)

2.	Diseases caused by uncoupling from the ER export machinery, preventing ubiquitination and degradation of mutant proteins by proteasomes, leading to an accumulation of mutant proteins in the ER

3.	Diseases caused by defects in the cellular machinery that is needed for the transport of proteins from the ER to the Golgi complex.

UGGT plays an important role in correcting temperature sensitive misfolding events, through its involvement in the ER quality control system. Protein trafficking diseases result when mutations occur due to these misfolding events.

Therapeutic strategies have been developed to correct these misfolding events. These strategies include incubation of the misfolded proteins at a lower temperature (<30 °C), or treatment with a high concentration of osmolytes such as glycerol, trimethylamine, oxide, or 4-phenylbutyrate. Therapeutic small molecule correctors have also been developed, these correctors function as pharmacological chaperones binding directly to a mutant/misfolded protein and correcting folding. Small molecule correctors have been developed for multiple protein trafficking diseases, including cystic fibrosis. Other correctors can target cellular pathways, acting through proteostasis to improve protein folding.