DOLK

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred ER membrane localization, consistent with the experimentally demonstrated ER membrane localization of human dolichol kinase and its yeast ortholog SEC59. Reason: DOLK is an experimentally validated polytopic ER membrane protein (PMID:16923818), so the IBA localization is correct and represents a core aspect of where the enzyme acts. Supporting Evidence: PMID:16923818 shown to be a polytopic membrane protein localized in the endoplasmic reticulum with an N terminus extended into the lumen and a cytoplasmically oriented C terminus.
GO:0004168 dolichol kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred dolichol kinase activity, the defining and experimentally established molecular function of DOLK. Reason: This is the core molecular function of the gene, directly demonstrated biochemically (PMID:12213788, PMID:16923818) and by disease-variant enzyme assays (PMID:17273964, PMID:22242004). GOA carries this exact current term (GO:0004168, EC 2.7.1.108). Supporting Evidence: PMID:12213788 Dolichol kinase (DK) catalyzes the CTP-mediated phosphorylation of dolichol in eukaryotic cells, the terminal step in dolichyl monophosphate (Dol-P) biosynthesis de novo.
GO:0043048 dolichyl monophosphate biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in dolichyl monophosphate (Dol-P) biosynthesis, the pathway output of the dolichol kinase reaction. Reason: Dol-P biosynthesis is the direct biological process to which the DOLK reaction contributes; this is well supported experimentally and the IBA is at an appropriate level of specificity. Supporting Evidence: PMID:12213788 the terminal step in dolichyl monophosphate (Dol-P) biosynthesis de novo.
GO:0004168 dolichol kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated annotation of dolichol kinase activity from the RHEA/EC mapping (RHEA:13133, EC 2.7.1.108). Reason: The EC/RHEA mapping is exactly correct for DOLK and matches the experimentally established catalytic activity. The reaction is documented in UniProt. Supporting Evidence: file:human/DOLK/DOLK-uniprot.txt Reaction=a di-trans,poly-cis-dolichol + CTP = a di-trans,poly-cis-
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Automated ER membrane localization from the UniProt subcellular-location keyword mapping, consistent with experimental data. Reason: DOLK is an experimentally confirmed integral ER membrane protein; the SubCell mapping is accurate. Supporting Evidence: file:human/DOLK/DOLK-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Interactor identified in a proteome-scale binary interactome map. The generic "protein binding" term is uninformative about DOLK's actual molecular function. Reason: This annotation comes from a large-scale high-throughput interactome screen and only asserts the uninformative term GO:0005515 protein binding. Per curation guidelines this term should not be treated as core function; the physiologically meaningful function is dolichol kinase activity. Retained as an experimental IPI rather than removed. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: Interactor reported in a large-scale alternative-splicing interactome study; the term is uninformative for DOLK function. Reason: High-throughput protein-protein interaction annotation using the generic GO:0005515 term. It does not inform the molecular function of DOLK and is not a core annotation. Retained as an experimental IPI. Supporting Evidence: PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Interactors reported in a large-scale interactome map (e.g. KCNA6, LRRC4C); the generic term is uninformative for DOLK function. Reason: High-throughput interactome annotation using the uninformative GO:0005515 term. DOLK's interactors here are largely co-resident ER membrane proteins and the binding data do not establish a specific molecular function. Retained as an experimental IPI. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Multiple interactors reported in the HuRI binary interactome map; the generic term is uninformative for DOLK function. Reason: High-throughput binary interactome annotation using the uninformative GO:0005515 term. The many interactors (largely ER/membrane proteins) do not define a specific molecular function for DOLK. Retained as an experimental IPI. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Interactors reported in a proteome-scale AP-MS network study; the generic term is uninformative for DOLK function. Reason: High-throughput proteome-scale interaction annotation using the uninformative GO:0005515 term. Does not inform DOLK molecular function and is not core. Retained as an experimental IPI. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0043048 dolichyl monophosphate biosynthetic process	TAS Reactome:R-HSA-446199	ACCEPT	Summary: Reactome-asserted involvement in dolichyl phosphate synthesis, matching the enzyme's pathway role. Reason: DOLK catalyzes the terminal step producing Dol-P; the Reactome pathway "Synthesis of dolichyl-phosphate" correctly captures this biological process. Supporting Evidence: PMID:12213788 the terminal step in dolichyl monophosphate (Dol-P) biosynthesis de novo.
GO:0004168 dolichol kinase activity	TAS Reactome:R-HSA-446195	ACCEPT	Summary: Reactome-asserted dolichol kinase activity (DOLK phosphorylates dolichol to Dol-P), matching the core molecular function. Reason: Correct assignment of the enzyme's defining catalytic activity, corroborated by biochemical assays. Supporting Evidence: PMID:16923818 Human dolichol kinase, a polytopic endoplasmic reticulum membrane protein with a cytoplasmically oriented CTP-binding site.
GO:0004168 dolichol kinase activity	TAS Reactome:R-HSA-4755600	ACCEPT	Summary: Reactome-asserted dolichol kinase activity (disease-annotated reaction), matching the core molecular function. Reason: Correct assignment of the defining catalytic activity of DOLK. Supporting Evidence: PMID:16923818 Human dolichol kinase, a polytopic endoplasmic reticulum membrane protein with a cytoplasmically oriented CTP-binding site.
GO:0005730 nucleolus	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Single high-throughput immunofluorescence (HPA) annotation to the nucleolus, inconsistent with the well-established integral ER membrane localization of this polytopic membrane kinase. Reason: DOLK is a ~15-pass integral ER membrane protein (PMID:16923818); a nucleolar localization is biologically implausible for its function and is contradicted by IDA, IBA, IEA and Reactome ER membrane annotations. This is most likely background/off-target signal in the HPA immunofluorescence screen. Not removed (single experimental IF datum) but flagged as over-annotation. Supporting Evidence: PMID:16923818 shown to be a polytopic membrane protein localized in the endoplasmic reticulum with an N terminus extended into the lumen and a cytoplasmically oriented C terminus.
GO:0043048 dolichyl monophosphate biosynthetic process	IGI PMID:12213788 Expression and characterization of a human cDNA that complem...	ACCEPT	Summary: Genetic interaction evidence: human DOLK (hDK1) complements the yeast sec59-1 (SEC59/dolichol kinase) mutant, restoring dolichol kinase activity, Dol-P levels and N-glycosylation, establishing its role in Dol-P biosynthesis. Reason: Cross-species complementation (with yeast SEC59, UniProtKB:P20048) demonstrates DOLK functions in de novo Dol-P biosynthesis. This is a well-supported core biological process annotation. Supporting Evidence: PMID:12213788 hDK1 is capable of complementing the growth defect, elevating DK activity, and consequently increasing Dol-P levels in vivo and restoring normal N-glycosylation of carboxypeptidase Y at the restrictive temperature in the temperature-sensitive mutant sec59-1.
GO:0004168 dolichol kinase activity	EXP PMID:17273964 A defect in dolichol phosphate biosynthesis causes a new inh...	ACCEPT	Summary: Experimental demonstration of dolichol kinase activity via disease-variant characterization: CDG1M variants Cys99Ser and Tyr441Ser have only 2-4% residual DK activity. Reason: Direct experimental measurement of the enzyme's catalytic activity in patient cells and by yeast complementation; core molecular function. Supporting Evidence: PMID:17273964 The residual activity of mutant DK1 was 2%-4% when compared with control cells.
GO:0004168 dolichol kinase activity	IMP PMID:22242004 Autosomal recessive dilated cardiomyopathy due to DOLK mutat...	ACCEPT	Summary: Mutant-phenotype evidence: pathogenic DOLK mutations cause a dolichol kinase deficiency confirmed by enzyme analysis in patient fibroblasts. Reason: Loss of catalytic activity upon mutation directly supports the dolichol kinase molecular function of DOLK; core. Supporting Evidence: PMID:22242004 Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families.
GO:0043048 dolichyl monophosphate biosynthetic process	IMP PMID:22242004 Autosomal recessive dilated cardiomyopathy due to DOLK mutat...	ACCEPT	Summary: Mutant-phenotype evidence that DOLK is required for dolichol-phosphate formation; DOLK mutations abolish dolichol kinase activity and downstream glycosylation. Reason: DOLK mutations cause deficient formation of dolichol-phosphate and impaired N-glycosylation / O-mannosylation, supporting its role in Dol-P biosynthesis. Core biological process. Supporting Evidence: PMID:22242004 pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-4755600	ACCEPT	Summary: Reactome-asserted ER membrane localization, consistent with experimental data. Reason: Correct; matches the experimentally established ER membrane localization of DOLK. Supporting Evidence: PMID:16923818 localized in the endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-446195	ACCEPT	Summary: Reactome-asserted ER membrane localization, consistent with experimental data. Reason: Correct; matches the experimentally established ER membrane localization of DOLK. Supporting Evidence: PMID:16923818 localized in the endoplasmic reticulum
GO:0004168 dolichol kinase activity	IDA PMID:12213788 Expression and characterization of a human cDNA that complem...	ACCEPT	Summary: Direct assay evidence: overexpression of human DOLK (hDK1) increased dolichol kinase activity ~15-fold in microsomes and complemented the yeast DK-deficient mutant. Reason: Biochemical demonstration of the enzyme's catalytic activity; the defining and core molecular function. Supporting Evidence: PMID:12213788 overexpression of hDK1p in Sf-9 cells resulted in a 15-fold increase in DK activity but not DAG kinase activity in crude microsomal fractions.
GO:0004168 dolichol kinase activity	IDA PMID:16923818 Human dolichol kinase, a polytopic endoplasmic reticulum mem...	ACCEPT	Summary: Direct assay evidence with mapping of the CTP-binding site and kinetics (KM 22.8 uM dolichol; 3.5 uM CTP); G443D abolishes activity. Reason: Detailed biochemical characterization of DOLK's dolichol kinase activity; core molecular function. Supporting Evidence: file:human/DOLK/DOLK-uniprot.txt KM=22.8 uM for dolichol {ECO:0000269\|PubMed:16923818};
GO:0043048 dolichyl monophosphate biosynthetic process	IDA PMID:12213788 Expression and characterization of a human cDNA that complem...	ACCEPT	Summary: Direct evidence that DOLK produces Dol-P: expression elevates DK activity and increases in vivo Dol-P levels, restoring N-glycosylation. Reason: DOLK catalyzes the terminal step of Dol-P biosynthesis; increased Dol-P upon expression directly supports this process. Core. Supporting Evidence: PMID:12213788 elevating DK activity, and consequently increasing Dol-P levels in vivo
GO:0043048 dolichyl monophosphate biosynthetic process	IDA PMID:16923818 Human dolichol kinase, a polytopic endoplasmic reticulum mem...	ACCEPT	Summary: Direct evidence linking DOLK catalytic activity to dolichyl monophosphate biosynthesis, with functional mapping of catalytic residues. Reason: DOLK catalyzes CTP-dependent dolichol phosphorylation, the terminal step of Dol-P biosynthesis; mutations abolishing activity confirm the requirement. Core. Supporting Evidence: PMID:16923818 Dolichol kinase (DK) catalyzes the CTP-dependent phosphorylation of dolichol in the biosynthesis de novo and possibly the recycling of dolichyl monophosphate
GO:0005789 endoplasmic reticulum membrane	IDA PMID:16923818 Human dolichol kinase, a polytopic endoplasmic reticulum mem...	ACCEPT	Summary: Direct assay evidence that human DOLK is a polytopic ER membrane protein, from overexpression and topology mapping in CHO cells. Reason: Experimentally demonstrated ER membrane localization by the primary characterization paper; this is the core location where DOLK acts. Supporting Evidence: PMID:16923818 shown to be a polytopic membrane protein localized in the endoplasmic reticulum with an N terminus extended into the lumen and a cytoplasmically oriented C terminus.
GO:0006488 dolichol-linked oligosaccharide biosynthetic process	IGI PMID:12213788 Expression and characterization of a human cDNA that complem...	NEW	Summary: Proposed annotation capturing DOLK's role in supplying Dol-P for assembly of the dolichol-linked oligosaccharide (LLO) used in N-glycosylation. DOLK complementation of the yeast dolichol kinase mutant restores N-glycosylation, demonstrating this downstream involvement. Reason: The existing GOA BP annotations stop at dolichyl monophosphate biosynthesis (GO:0043048). DOLK is upstream of, and required for, LLO assembly for protein N-linked glycosylation; adding GO:0006488 records this downstream biological role explicitly, supported by rescue of N-glycosylation in the yeast complementation assay. Supporting Evidence: PMID:12213788 restoring normal N-glycosylation of carboxypeptidase Y at the restrictive temperature in the temperature-sensitive mutant sec59-1.

Gene Description

Existing Annotations Review

Core Functions

CTP-dependent dolichol kinase activity: phosphorylates dolichol to dolichyl monophosphate (Dol-P) at the ER membrane, the terminal step of de novo Dol-P biosynthesis (EC 2.7.1.108).

Supplies dolichyl monophosphate, the activated lipid carrier that primes assembly of the dolichol-linked oligosaccharide for protein N-linked glycosylation (and is also required for O-/C-mannosylation and GPI-anchor biosynthesis).

References

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