MPDU1 (Lec35; suppressor of Lec15 and Lec35 glycosylation mutation homolog, SL15) is a polytopic endoplasmic reticulum membrane protein of the MPDU1/PQ-loop family that is required for efficient utilization of the lipid-linked monosaccharide donors dolichyl-phosphate-mannose (Dol-P-Man) and dolichyl-phosphate-glucose (Dol-P-Glc) on the lumenal side of the ER. It is not itself a glycosyltransferase and has no known catalytic activity; rather it acts as a utilization/presentation factor that makes the mannosyl and glucosyl groups of these donors available to the lumenal glycosyltransferases, controlling an aspect of donor orientation in the ER membrane. Through this role it supports mannosylation and glucosylation steps of dolichol-linked oligosaccharide (lipid-linked oligosaccharide, LLO) assembly in protein N-glycosylation, as well as GPI-anchor biosynthesis and protein O- and C-mannosylation. Loss of function causes MPDU1-CDG (congenital disorder of glycosylation type If), a multisystem disorder featuring under-glycosylation of serum glycoproteins with skin (ichthyosis), neurological and visual involvement.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009312 oligosaccharide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAN-GO phylogenetic (IBA) annotation to the general parent term for oligosaccharide biosynthesis. This is consistent with MPDU1's established role in dolichol-linked oligosaccharide (LLO) assembly; it is broader than the experimentally supported child term GO:0006488 (dolichol-linked oligosaccharide biosynthetic process), but a correct, conservative phylogenetic call. Reason: The IBA call is correct at the family level and has been through phylogenetic review. It is retained at its (general) level; the more specific process the experimental evidence supports is captured by the separate GO:0006488 annotation. Kept as a conservative phylogenetic annotation rather than second-guessed. Supporting Evidence: PMID:11179430 The Lec35 gene product (Lec35p) is required for utilization of the mannose donor |
| GO:0016020 membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Electronic mapping from the UniProt subcellular-location vocabulary to the generic term "membrane". MPDU1 is indeed a multi-pass membrane protein, but its specific residence is the ER membrane (GO:0005789). Reason: Not wrong, but "membrane" is an uninformative parent superseded by the more specific and evidenced GO:0005789 (endoplasmic reticulum membrane). Retained as an over-annotated generic location. Supporting Evidence: PMID:11179430 predicts a novel endoplasmic reticulum membrane protein |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary interaction with MANBAL (Q9NQG1) reported in the HuRI human interactome map. This interaction is independently recorded in the UniProt entry (O75352; Q9NQG1: MANBAL; NbExp=3). However, the annotated term is the uninformative generic "protein binding". Reason: "protein binding" (GO:0005515) is too generic to convey MPDU1's molecular role, per curation guidelines. The interaction with MANBAL is genuine and physiologically plausible (a small ER-membrane protein of unclear function), but this bare-binding term does not describe MPDU1's function; the underlying experimental IPI is retained rather than removed. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions file:human/MPDU1/MPDU1-uniprot.txt O75352; Q9NQG1: MANBAL |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence-based localization to mitochondrion. This conflicts with the well-established ER-membrane residence of MPDU1 (a Dol-P-Man/Dol-P-Glc utilization factor of ER-lumenal glycosylation) and with its MPDU1/PQ-loop family membership; no functional evidence supports a mitochondrial role. Reason: Likely reflects immunofluorescence cross-reactivity or partial signal rather than a genuine mitochondrial function. Because this is an experimental (IDA) HPA annotation whose primary images were not reviewed, it is flagged as over-annotated rather than removed; the ER membrane is the functionally relevant location. Supporting Evidence: PMID:11179430 predicts a novel endoplasmic reticulum membrane protein |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localization to the endoplasmic reticulum, consistent with the established biology of MPDU1/Lec35 as an ER protein required for utilization of dolichol-phosphate sugar donors in ER-lumenal glycosylation. Reason: Correct localization. Slightly broader than the specific ER-membrane term but accurate and independently supported; retained. Supporting Evidence: PMID:11179430 predicts a novel endoplasmic reticulum membrane protein |
| GO:0009312 oligosaccharide biosynthetic process | IGI PMID:11733564 MPDU1 mutations underlie a novel human congenital disorder o... | MODIFY | Summary: Genetic-interaction evidence from the CDG-If study: MPDU1 mutations cause accumulation of incomplete lipid-linked oligosaccharide precursors, and expression of normal Lec35 cDNA restores normal LLO biosynthesis. The essence is correct but the term is the general parent. Reason: The supporting genetics specifically concern dolichol-linked (lipid-linked) oligosaccharide biosynthesis, so the more specific child term GO:0006488 is the appropriate annotation. Proposed replacements: dolichol-linked oligosaccharide biosynthetic process Supporting Evidence: PMID:11733564 Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis |
| GO:0005515 protein binding | IPI PMID:16237761 Screening of hepatocyte proteins binding to F protein of hep... | MARK AS OVER ANNOTATED | Summary: IPI derived from a yeast two-hybrid screen of a liver cDNA library for proteins binding the hepatitis C virus F (ARFP) protein (bait UniProtKB:P0C045). MPDU1 was captured as a prey. The annotated term is the uninformative generic "protein binding" and the interaction is with a viral protein of uncertain relevance to MPDU1's cellular function. Reason: Bare "protein binding" (GO:0005515) does not describe MPDU1's molecular function, and a single Y2H hit against a viral bait is weak, non-core evidence. Per curation policy the underlying experimental IPI is not removed but is flagged as an uninformative over-annotation. Supporting Evidence: PMID:16237761 yeast two-hybrid system is an effective method for identifying hepatocyte proteins interacting with F protein of hepatitis C virus |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput mass-spectrometry detection of MPDU1 in the membrane proteome of an NK-like cell line. Confirms MPDU1 is a membrane protein but only to the generic "membrane" term. Reason: Consistent with MPDU1 being an integral membrane protein, but "membrane" is generic and superseded by the specific ER membrane location (GO:0005789). A proteome-scale MS membrane-preparation hit does not localize the protein to a specific compartment. Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:11179430 Requirement of the Lec35 gene for all known classes of monos... | ACCEPT | Summary: MPDU1/Lec35 is an ER membrane protein; the founding functional paper predicts a novel ER membrane protein and localizes its activity (controlling Dol-P-Man orientation) to the ER membrane. This is the specific, functionally relevant location. Reason: Correct and specific core location, corroborated by HPA IDA (ER) and by the multi-pass membrane topology. This is the preferred CC term over generic "membrane". Supporting Evidence: PMID:11179430 predicts a novel endoplasmic reticulum membrane protein PMID:11179430 Lec35p controls an aspect of MPD orientation in the endoplasmic reticulum membrane that is crucial for its activity as a donor substrate |
| GO:0006457 protein folding | NAS PMID:11179430 Requirement of the Lec35 gene for all known classes of monos... | MARK AS OVER ANNOTATED | Summary: Annotation reflecting that MPDU1-supported N-glycosylation is important for downstream glycoprotein folding (the source paper notes that LLOs are important for protein folding). This is a downstream consequence, not MPDU1's molecular role. Reason: MPDU1 does not act in the protein-folding machinery; it enables use of dolichol-P sugar donors for glycan assembly, and correct N-glycosylation in turn supports glycoprotein folding. Annotating MPDU1 directly to protein folding over-attributes a distal, indirect effect and is better captured by its glycosylation-biosynthesis annotations. Supporting Evidence: PMID:11179430 important for functions such as protein folding and membrane anchoring |
| GO:0006488 dolichol-linked oligosaccharide biosynthetic process | TAS PMID:11733564 MPDU1 mutations underlie a novel human congenital disorder o... | ACCEPT | Summary: Core biological process: MPDU1/Lec35 is required for utilization of dolichylphosphomannose and dolichylphosphoglucose in assembly of the dolichol-linked (lipid-linked) oligosaccharide precursor for N-glycosylation; CDG-If patients accumulate incomplete LLO precursors and normal LLO biosynthesis is restored by Lec35 cDNA. Reason: Directly supported and represents the specific, core biological process of MPDU1. Supporting Evidence: PMID:11733564 accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation PMID:11179430 glucose-P-dolichol (GPD)-dependent glucosylation of LLO. Both were found to require Lec35p |
| GO:0009312 oligosaccharide biosynthetic process | IDA PMID:11179430 Requirement of the Lec35 gene for all known classes of monos... | MODIFY | Summary: IDA to the general parent term based on the demonstration that Lec35p is required for utilization of the mannose donor (MPD) in synthesis of lipid-linked oligosaccharides. Correct in essence but too general. Reason: The experimental evidence concerns dolichol-linked (lipid-linked) oligosaccharide assembly specifically, so the more precise child term GO:0006488 should be used. Proposed replacements: dolichol-linked oligosaccharide biosynthetic process Supporting Evidence: PMID:11179430 The Lec35 gene product (Lec35p) is required for utilization of the mannose donor |
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