Asialoglycoprotein receptor 1 (ASGR1, also known as hepatic lectin H1 or HL-1) is a 291-amino-acid single-pass type II transmembrane C-type lectin that serves as the major subunit of the hepatic asialoglycoprotein receptor (Ashwell-Morell receptor) on the sinusoidal (basolateral) plasma membrane of hepatocytes. ASGR1 comprises an N-terminal cytoplasmic tail (residues 1-40) harboring a canonical tyrosine-based clathrin-coated pit internalization signal (YQDL, residues 5-8) and a palmitoylated cysteine (Cys-36), a single transmembrane signal-anchor helix (residues 41-61), an extracellular coiled-coil stalk region (residues 61-123) that mediates assembly into homo-oligomers and hetero-oligomers with the minor subunit ASGR2 (H2), and a C-terminal extracellular C-type lectin carbohydrate-recognition domain (residues 161-278). Its carbohydrate-recognition domain coordinates three calcium ions and carries a conserved QPD (Gln240-Pro241-Asp242) motif that specifically recognizes terminal D-galactose and N-acetyl-D-galactosamine (GalNAc) residues on desialylated plasma glycoproteins. Upon ligand binding at the external face of the hepatocyte plasma membrane, ASGR1 mediates clathrin-dependent receptor-mediated endocytosis of cargo into sorting endosomes, where acidification and Ca2+ depletion trigger ligand dissociation for lysosomal degradation while the receptor recycles to the cell surface. In addition to the canonical membrane-anchored isoform H1a (P07306-1), an alternatively spliced isoform H1b (P07306-2) lacking the transmembrane region is secreted as soluble asialoglycoprotein receptor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004873 asialoglycoprotein receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based transfer of asialoglycoprotein receptor activity from rat Asgr1 (P02706), capturing the core molecular function of human ASGR1. Reason: ASGR1 is the major subunit (H1) of the hepatic asialoglycoprotein receptor and directly binds terminal D-galactose and N-acetyl-D-galactosamine (GalNAc) residues on desialylated glycoproteins via its QPD-motif C-type lectin domain. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. PMID:8439566 Hepatic lectins (asialoglycoprotein receptors) specifically recognize galactose-terminated glycoproteins and mediate endocytosis of these molecules. |
| GO:0004873 asialoglycoprotein receptor activity | TAS PMID:8439566 Determination of mouse major asialoglycoprotein receptor cDN... | ACCEPT | Summary: Traceable author statement confirming asialoglycoprotein receptor activity. Reason: This is the defining core molecular function of ASGR1, which binds galactose- and GalNAc-terminated desialylated glycoproteins and mediates their endocytic uptake. Supporting Evidence: PMID:8439566 Hepatic lectins (asialoglycoprotein receptors) specifically recognize galactose-terminated glycoproteins and mediate endocytosis of these molecules. |
| GO:0005515 protein binding | IPI PMID:11543633 Cloning, mapping, and characterization of a human homologue ... | REMOVE | Summary: Yeast two-hybrid and pull-down interaction with LASS2/CERS2 (Q96G23); bare GO:0005515 is removed as uninformative per repository policy. Reason: Bare GO:0005515 (protein binding) from yeast two-hybrid and GST pull-down screening with LASS2/CERS2 (Q96G23) is uninformative and is removed under the repository's protein-binding policy. Supporting Evidence: PMID:11543633 Yeast two-hybrid screening and glutathione S-transferase pull-down assays showed that the LASS2 protein interacts with several membrane-associated receptors or transporters. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: High-throughput human liver yeast two-hybrid interaction with CERS2 (Q96G23); bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and is removed under the repository's protein-binding policy. Supporting Evidence: PMID:21988832 In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:A8MZ59; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:O14524-2; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:O95471; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P00387; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P12314; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P24593; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P31937; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P43628; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:P62952; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q13113; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q14973; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q5JX71; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q6ZMZ0; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q7Z7G2; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q86WK6; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q8IVF2-3; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q8IX19; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q8TBE3; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q8TED1; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q96BA8; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q96BI3; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q96L08; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9H7M9; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9NPE6; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9NQQ7-3; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9NR31; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9UN42; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9Y282; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput yeast two-hybrid interaction (HuRI) with UniProtKB:Q9Y320; bare GO:0005515 is removed per repository policy. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid interactome screening is uninformative and removed under the repository's protein-binding policy. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005537 D-mannose binding | IBA GO_REF:0000033 | REMOVE | Summary: OVER_PROPAGATED: D-mannose binding propagated from PANTHER node PTN004568004 (seeded by CLEC17A/Q6ZS10); ASGR1 carries a galactose-specific QPD motif and specifically binds terminal D-galactose and N-acetyl-D-galactosamine rather than D-mannose. Reason: The PAINT annotation at PANTHER node PTN004568004 (within PTHR22803) is seeded by human CLEC17A (UniProtKB:Q6ZS10, prolectin), which binds terminal mannose and fucose. Unlike EPN-motif mannose-binding C-type lectins, ASGR1 contains the canonical galactose-recognizing QPD tripeptide (Gln240-Pro241-Asp242) in its carbohydrate-recognition domain and selectively binds terminal D-galactose and N-acetyl-D-galactosamine (GalNAc) on desialylated glycoproteins. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN004568004 · PTN004568004 SUPPORTS SOURCE BUT NOT TARGET Ancestral node in PANTHER family PTHR22803 combines mannose/fucose-binding and galactose/GalNAc-binding C-type lectin paralogs. UniProtKB:Q6ZS10 · CLEC17A SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC17A (prolectin), a mannose/fucose-binding C-type lectin whose glycan specificity does not transfer to the QPD-motif galactose/GalNAc receptor ASGR1. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | MODIFY | Summary: Reflects the alternatively spliced soluble isoform H1b (P07306-2), in which residues 24-63 spanning the transmembrane domain are replaced by a single Asp (VSP_044480) and the protein is secreted by hepatocytes into the extracellular space; refined to GO:0005615 (extracellular space). Reason: Whereas canonical ASGR1 isoform H1a (P07306-1) is an integral plasma membrane receptor that mediates endocytosis, splice isoform H1b (P07306-2) replaces residues 24-63 (the transmembrane signal-anchor) with a single Asp residue (VSP_044480) and is secreted into the extracellular space. Because GO:0005576 (extracellular region) is broader than warranted for a soluble secreted protein, it is refined via MODIFY to its more specific descendant GO:0005615 (extracellular space). Proposed replacements: extracellular space Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt [Isoform H1b]: Secreted {ECO:0000269|PubMed:20886072}. |
| GO:0005886 plasma membrane | EXP PMID:12171918 Nonpalmitoylated human asialoglycoprotein receptors recycle ... | ACCEPT | Summary: Experimental localization of human ASGR1 (H1) to the plasma membrane where it internalizes desialylated glycoprotein ligands via clathrin-coated pits. Reason: ASGR1 functions at the hepatocyte plasma membrane as a single-pass type II transmembrane endocytic receptor. Supporting Evidence: PMID:12171918 The hepatic asialoglycoprotein receptor (ASGP-R) internalizes desialylated glycoproteins via the clathrin-coated pit pathway and mediates their delivery to lysosomes for degradation. The human ASGP-R contains two subunits, H1 and H2. file:genes/human/ASGR1/ASGR1-uniprot.txt [Isoform H1a]: Cell membrane {ECO:0000269|PubMed:12171918}; Single-pass type II membrane protein. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Keyword-based mapping from UniProt Subcellular Location Cell membrane (SL-0039) to plasma membrane. Reason: Consistent with experimental evidence establishing the plasma membrane as the site where ASGR1 binds and internalizes desialylated glycoproteins. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt [Isoform H1a]: Cell membrane {ECO:0000269|PubMed:12171918}; Single-pass type II membrane protein. |
| GO:0005886 plasma membrane | TAS PMID:10734069 Basolateral sorting signals differ in their ability to redir... | ACCEPT | Summary: Demonstrates basolateral plasma membrane localization and sorting of ASGR1 (H1) in polarized epithelial cells. Reason: Confirms that ASGR1 localizes to the basolateral plasma membrane, matching its physiological localization on the sinusoidal surface of hepatocytes. Supporting Evidence: PMID:10734069 We have generated chimeric proteins with the cytoplasmic domain of either the asialoglycoprotein receptor H1 or the transferrin receptor, two basolateral proteins, fused to the transmembrane and exoplasmic segments of aminopeptidase N, an apical protein, and analyzed them in Madin-Darby canine kidney cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8855711 | ACCEPT | Summary: Reactome pathway assertion placing the ASGR1/ASGR2 complex at the hepatocyte plasma membrane. Reason: Accurate core localization of the functional ASGR1/ASGR2 receptor complex. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt [Isoform H1a]: Cell membrane {ECO:0000269|PubMed:12171918}; Single-pass type II membrane protein. |
| GO:0006898 receptor-mediated endocytosis | IDA PMID:29069408 Asialoglycoprotein receptor 1 mediates productive uptake of ... | ACCEPT | Summary: Direct experimental demonstration that ASGR1 mediates receptor-mediated endocytosis of GalNAc-conjugated and unconjugated antisense oligonucleotides in hepatocytes. Reason: Receptor-mediated endocytosis of Gal/GalNAc-terminated ligands via clathrin-coated pits is the core biological process executed by ASGR1. Supporting Evidence: PMID:29069408 GalNAc conjugation confers high affinity binding to the Asialoglycoprotein Receptor (ASGR), a cell surface C-type lectin that functions as a scavenger receptor and is able to remove desialylated glycoproteins from circulation |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:8439566 Determination of mouse major asialoglycoprotein receptor cDN... | ACCEPT | Summary: Traceable author statement confirming that hepatic asialoglycoprotein receptors mediate endocytosis of galactose-terminated glycoproteins. Reason: Captures the core physiological role of ASGR1 in clearing desialylated glycoproteins from circulation by receptor-mediated endocytosis. Supporting Evidence: PMID:8439566 Hepatic lectins (asialoglycoprotein receptors) specifically recognize galactose-terminated glycoproteins and mediate endocytosis of these molecules. |
| GO:0006955 immune response | IBA GO_REF:0000033 | REMOVE | Summary: OVER_PROPAGATED: Immune response propagated from PANTHER node PTN001105054 seeded by myeloid C-type lectin pattern-recognition receptors (Clec4e, CLEC4D, Cd209b/d), FCER2, and invertebrate lectins; ASGR1 is a hepatocyte endocytic scavenger receptor for endogenous desialylated plasma glycoproteins, not an immune receptor. Reason: PANTHER node PTN001105054 in family PTHR22803 groups hepatic asialoglycoprotein receptor subunits (ASGR1/ASGR2) with myeloid innate immune C-type lectin receptors (Clec4e/Mincle, CLEC4D/MCL, SIGN-R1/Cd209b, SIGN-R3/Cd209d), the low-affinity IgE Fc receptor FCER2 (P06734), and invertebrate/teleost C-type lectins. ASGR1 functions on hepatocytes to clear endogenous desialylated serum glycoproteins and aged desialylated platelets via clathrin-mediated endocytosis, coupling platelet clearance to hepatic thrombopoietin (TPO) regulation via JAK2-STAT3 signaling; this homeostatic glycoprotein and platelet turnover is not directly involved in an immune response (GO:0006955). Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN001105054 · PTN001105054 SUPPORTS SOURCE BUT NOT TARGET Ancestral node in PANTHER family PTHR22803 spans both myeloid immune C-type lectins and hepatic asialoglycoprotein receptors. UniProtKB:P06734 · FCER2 SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human low-affinity IgE Fc receptor (FCER2/CD23), an immune receptor paralog whose immune function does not transfer to ASGR1. UniProtKB:Q8WXI8 · CLEC4D SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC4D (MCL), a myeloid innate-immune C-type lectin paralog. MGI:MGI:1298389 · Clec4e SUPPORTS SOURCE BUT NOT TARGET Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (Q9R0Q8, mouse Clec4e/Mincle); myeloid innate-immune C-type lectin paralog. MGI:MGI:1861231 · Cd209b SUPPORTS SOURCE BUT NOT TARGET Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (Q8CJ91, mouse Cd209b/SIGN-R1); innate-immune C-type lectin paralog. MGI:MGI:1861232 · Cd209d SUPPORTS SOURCE BUT NOT TARGET Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (Q91ZW8, mouse Cd209d/SIGN-R3); innate-immune C-type lectin paralog. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Plays thereby a role in a variety of physiological processes, such as removal of desialylated platelets, elimination of activated lymphocytes and maintenance of serum glycoprotein homeostasis (PubMed:25485912). Plays a role in the removal of desialylated platelets by activating a feedback loop regulating thrombopoietin (TPO) expression via the JAK2-STAT3 signaling pathway (PubMed:25485912). |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference from PANTHER node PTN001105053 placing the receptor ectodomain on the external side of the plasma membrane. Reason: ASGR1 is a single-pass type II plasma membrane protein whose C-terminal coiled-coil stalk and C-type lectin carbohydrate-recognition domain (residues 62-291) project into the extracellular space on the external side of the hepatocyte plasma membrane to bind circulating desialylated glycoproteins. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001105053 · PTN001105053 SUPPORTS TRANSFER Type II transmembrane topology with an extracellular C-terminal C-type lectin domain on the external face of the plasma membrane is conserved across this clade of cell-surface C-type lectin receptors. UniProtKB:Q9NNX6 · CD209 SUPPORTS TRANSFER Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CD209 (DC-SIGN), a fellow type II cell-surface C-type lectin receptor. MGI:MGI:1916415 · Clec10a SUPPORTS TRANSFER Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (P49300, mouse Clec10a), a closely related galactose/GalNAc-specific type II cell-surface C-type lectin. MGI:MGI:95497 · Fcer2a SUPPORTS TRANSFER Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (P20693, mouse Fcer2), a fellow type II cell-surface C-type lectin. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt [Isoform H1a]: Cell membrane {ECO:0000269|PubMed:12171918}; Single-pass type II membrane protein. PMID:29069408 GalNAc conjugation confers high affinity binding to the Asialoglycoprotein Receptor (ASGR), a cell surface C-type lectin that functions as a scavenger receptor and is able to remove desialylated glycoproteins from circulation |
| GO:0038187 pattern recognition receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: OVER_PROPAGATED: Pattern recognition receptor activity propagated from PANTHER node PTN001105054 seeded by myeloid innate-immune C-type lectin receptors; ASGR1 is a hepatocyte receptor for endogenous desialylated plasma glycoproteins rather than a pathogen pattern-recognition receptor. Reason: PAINT propagated GO:0038187 (pattern recognition receptor activity) across PANTHER node PTN001105054 in family PTHR22803 from human and mouse myeloid pattern recognition receptors (CLEC6A/Dectin-2, CLEC4D/MCL, CLEC4E/Mincle, Cd209b/d). ASGR1 has functionally diverged as a hepatocyte-specific house-keeping receptor (GO:0004873, asialoglycoprotein receptor activity) that recognizes terminal galactose/GalNAc on endogenous desialylated serum glycoproteins for clearance and does not function as a pattern recognition receptor. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN001105054 · PTN001105054 SUPPORTS SOURCE BUT NOT TARGET Ancestral node in PTHR22803 conflates myeloid PRR C-type lectins with hepatic asialoglycoprotein receptors. UniProtKB:Q6EIG7 · CLEC6A SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC6A (Dectin-2), a bona fide myeloid pattern-recognition receptor. UniProtKB:Q8WXI8 · CLEC4D SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC4D (MCL), a bona fide myeloid pattern-recognition receptor. UniProtKB:Q9ULY5 · CLEC4E SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC4E (Mincle), a bona fide myeloid pattern-recognition receptor. MGI:MGI:1861231 · Cd209b SUPPORTS SOURCE BUT NOT TARGET Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (Q8CJ91, mouse Cd209b/SIGN-R1), an innate-immune pattern-recognition receptor. MGI:MGI:1861232 · Cd209d SUPPORTS SOURCE BUT NOT TARGET Corroborated in interpro/panther/PTHR22803/PTHR22803-entries.csv (Q91ZW8, mouse Cd209d/SIGN-R3), an innate-immune pattern-recognition receptor. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. |
| GO:0038187 pattern recognition receptor activity | IDA PMID:29069408 Asialoglycoprotein receptor 1 mediates productive uptake of ... | REMOVE | Summary: Mis-annotation of synthetic antisense oligonucleotide (ASO) uptake in PMID:29069408 as innate-immune pattern recognition receptor activity. Reason: Full-text inspection of PMID:29069408 shows that the study investigated ASGR1-mediated hepatocyte uptake of synthetic GalNAc-conjugated and unconjugated phosphorothioate antisense oligonucleotides (ASOs) and referred to ASGR1 in passing as a scavenger receptor for desialylated glycoproteins. The paper neither assayed pathogen-associated molecular patterns nor demonstrated innate-immune pattern recognition receptor activity (GO:0038187); the supported molecular function is GO:0004873 (asialoglycoprotein receptor activity). Supporting Evidence: PMID:29069408 GalNAc conjugation confers high affinity binding to the Asialoglycoprotein Receptor (ASGR), a cell surface C-type lectin that functions as a scavenger receptor and is able to remove desialylated glycoproteins from circulation |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Asgr1 (P34927) reflecting ASGR1 homo-oligomerization; retained as non-core structural property. Reason: Human ASGR1 self-associates via its extracellular coiled-coil neck region into functional homo-oligomers capable of mediating endocytic uptake of GalNAc-conjugated ligands independently of ASGR2, in addition to forming ASGR1/ASGR2 hetero-oligomers. Because homo-oligomerization is a structural assembly property supporting the receptor's core C-type lectin and endocytic receptor activities rather than a standalone molecular function in core_functions, it is retained as KEEP_AS_NON_CORE. Supporting Evidence: PMID:29069408 Interestingly, the parameters of conjugate uptake in cells expressing only ASGR1 were similar to those from cells expressing both ASGR1 and ASGR2, suggesting ASGR1 homooligomers are sufficient for GalNAc-mediated ASO uptake. |
| GO:0042806 fucose binding | IBA GO_REF:0000033 | REMOVE | Summary: OVER_PROPAGATED: Fucose binding propagated from PANTHER node PTN004568004 (seeded by CLEC17A/Q6ZS10); ASGR1 carries a QPD galactose/GalNAc-recognition motif and does not bind fucose. Reason: PAINT propagated GO:0042806 (fucose binding) from human CLEC17A (UniProtKB:Q6ZS10) at PANTHER node PTN004568004. ASGR1 possesses the galactose-specific QPD motif (Gln240-Pro241-Asp242) in its C-type lectin carbohydrate-recognition domain and specifically recognizes terminal D-galactose and N-acetyl-D-galactosamine (GalNAc) rather than L-fucose. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN004568004 · PTN004568004 SUPPORTS SOURCE BUT NOT TARGET Ancestral node in PANTHER family PTHR22803 combines mannose/fucose-binding and galactose/GalNAc-binding C-type lectin paralogs. UniProtKB:Q6ZS10 · CLEC17A SUPPORTS SOURCE BUT NOT TARGET Resolved in interpro/panther/PTHR22803/PTHR22803-entries.csv as human CLEC17A (prolectin), whose fucose-binding specificity does not transfer to the QPD-motif galactose/GalNAc receptor ASGR1. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. |
| GO:0005534 galactose binding | TAS PMID:8439566 Determination of mouse major asialoglycoprotein receptor cDN... | NEW | Summary: Proposed NEW annotation capturing the direct terminal D-galactose and N-acetyl-D-galactosamine (GalNAc) binding specificity of the ASGR1 QPD-motif C-type lectin domain. Reason: Whereas GO:0005537 (D-mannose binding) and GO:0042806 (fucose binding) are over-propagated from EPN-motif C-type lectin paralogs in PANTHER family PTHR22803 and removed, ASGR1 carries a canonical galactose-recognizing QPD motif (Gln240-Pro241-Asp242) in its C-type lectin carbohydrate-recognition domain and specifically binds terminal D-galactose and N-acetyl-D-galactosamine residues on desialylated plasma glycoproteins. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. PMID:8439566 Hepatic lectins (asialoglycoprotein receptors) specifically recognize galactose-terminated glycoproteins and mediate endocytosis of these molecules. |
| GO:0005509 calcium ion binding | TAS file:genes/human/ASGR1/ASGR1-uniprot.txt | NEW | Summary: Proposed NEW annotation for calcium ion coordination by the C-type lectin carbohydrate-recognition domain of ASGR1, which is required for carbohydrate ligand binding. Reason: The extracellular C-type lectin carbohydrate-recognition domain of ASGR1 coordinates three Ca2+ ions (UniProt FT BINDING Ca(2+) ligand_label 1, 2, and 3, including the QPD-motif Ca2+ ion at Gln240/Asp242/Glu253/Asn265/Asp266 labeled ligand_label 3 in UniProt) that directly coordinate terminal D-galactose and GalNAc ligands, and Ca2+ is required for ligand binding. Supporting Evidence: file:genes/human/ASGR1/ASGR1-uniprot.txt Calcium is required for ligand binding. file:genes/human/ASGR1/ASGR1-uniprot.txt FT BINDING 240 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT BINDING 242 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" |
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Download this section (compressed HTML)Q: What are the endogenous physiological glycoprotein substrates whose clearance by human ASGR1 homo-oligomers versus ASGR1/ASGR2 hetero-oligomers explains the cardioprotective reduction in non-HDL cholesterol observed in human ASGR1 loss-of-function heterozygotes?
Suggested experts: Paul H Weigel, Martin Spiess, Punit P Seth
Q: Does secreted soluble ASGR1 isoform H1b (sASGPR) act as a competitive decoy modulating hepatocyte clearance of desialylated glycoproteins in vivo?
Suggested experts: Martin Spiess
Experiment: Generate isogenic human hepatocyte lines expressing either ASGR1 alone or defined stoichiometric ratios of ASGR1 and ASGR2, and measure binding constants and clathrin-mediated internalization rates across a panel of defined multi-antennary Gal- and GalNAc-terminated glycopeptides and plasma glycoproteins.
Hypothesis: ASGR1 homo-oligomers and ASGR1/ASGR2 hetero-oligomers differ in their affinity and endocytic uptake kinetics for bi-, tri-, and tetra-antennary endogenous desialylated plasma glycoproteins.
Type: Surface plasmon resonance and quantitative live-cell endocytosis assay
Experiment: Perform acyl-biotin exchange and pulse-chase endocytosis imaging in primary human hepatocytes expressing wild-type versus C36S mutant ASGR1 to quantify clathrin adaptor AP-2 recruitment and endosomal ligand-receptor dissociation rates.
Hypothesis: Reversible S-palmitoylation of ASGR1 at Cys-36 dynamically regulates its partitioning into clathrin-coated pits and uncoupling of cargo in early sorting endosomes.
Type: Acyl-biotin exchange and live-cell TIRF/confocal microscopy
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