Glucosidase II and MRH-Domain Containing Proteins in the Secretory Pathway

Abstract

N -glycosylation in the endoplasmic reticulum (ER) consists of the transfer of a pre-assembled glycan conserved among species (Glc3Man9GlcNAc2) from a lipid donor to a consensus sequence within a nascent protein that is entering the ER. The protein-linked glycans are then processed by glycosidases and glycosyltransferases in the ER producing specific structures that serve as signalling molecules for the fate of the folding glycoprotein: to stay in the ER during the folding process, to be retrotranslocated to the cytosol for proteasomal degradation if irreversibly misfolded, or to pursue transit through the secretory pathway as a mature glycoprotein. In the ER, each glycan signalling structure is recognized by a specific lectin. A domain similar to that of the mannose 6-phosphate receptors (MPRs) has been identified in several proteins of the secretory pathway. These include the beta subunit of glucosidase II (GII), a key enzyme in the early processing of the transferred glycan that removes middle and innermost glucoses and is involved in quality control of glycoprotein folding in the ER (QC), the lectins OS-9 and XTP3-B, proteins involved in the delivery of ER misfolded proteins to degradation (ERAD), the gamma subunit of the Golgi GlcNAc-1-phosphotransferase, an enzyme involved in generating the mannose 6-phosphate (M6P) signal for sorting acidic hydrolases to lysosomes, and finally the MPRs that deliver those hydrolytic enzymes to the lysosome. Each of the MRH-containing proteins recognizes a different signalling N-glycan structure. Three-dimensional structures of some of the MRH domains have been solved, providing the basis to understand recognition mechanisms.

A sweet code for glycoprotein folding

“…GI is associated to the Sec61 αβγ translocon complex, ensuring the removal of the outermost glucose almost immediately after transfer of the N ‐glycan [10]. The α1,3‐exoglucosidase GII is an ER‐resident soluble heterodimer composed by a catalytic subunit (GIIα) non‐covalently bound to the GIIβ subunit [11–13]. GIIα displays the (G/F)(L/I/V/M)WXDMNE consensus sequence typical of glycosylhydrolase family 31.…”

Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology

“…The γ subunit contains an MRH (mannose-6-phosphate receptor homology) domain similar to those found in ER glucosidase II (16). Since many MRH domains act as lectins that bind both M6P modified and non-modified high mannose oligosaccharides, its presence in the γ subunit suggests that it might facilitate subunit ability to bind the N-glycans of hydrolases, thereby modulating the αβ’s recognition capability (17). It was also suggested that the MRH domain binds glycans on the α subunit, but a recent study demonstrated that interaction between the αβ and γ subunits is MRH-independent (18).…”

Glycoside Hydrolase MoGls2 Controls Asexual/Sexual Development, Cell Wall Integrity and Infectious Growth in the Rice Blast Fungus

“…Gls2 plays a key role in quality control of glycoprotein folding in ER, andis also responsible for the removal of the glucose added by UGGT. Cycles of deglucosylation and reglucosylation catalyzed by the opposing activities of UGGT and Gls2 continue until the glycoproteins acquire their native structure [15]. …”