Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic assignment of GO terms using logical inference, based on inter-ontology links
Combined Automated Annotation using Multiple IEA Methods
Defining the membrane proteome of NK cells.
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase.
Identification of a novel putative interaction partner of the nucleoporin ALADIN.
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PGRMC2 interacts with nucleoporin ALADIN (AAAS) and co-localizes at nuclear envelope and perinuclear ER.
"We detected that PGRMC2 co-localises with ALADIN and with different FG-repeat NUPs [...] to the nuclear envelope and the perinuclear ER."
Ligand and Target Discovery by Fragment-Based Screening in Human Cells.
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PGRMC2 identified as target for small molecules promoting adipocyte differentiation; binds heme-related molecules.
"our initial studies point to heme-related molecules as potential candidates to serve this function"
Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.
A reference map of the human binary protein interactome.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
OpenCell: Endogenous tagging for the cartography of human cellular organization.
The solute carrier superfamily interactome.
Cloning and tissue expression of two putative steroid membrane receptors.
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Original cloning of PGRMC2 (Dg6) as putative steroid receptor. Later research showed it is primarily a heme chaperone.
"The two proteins are the first putative steroid membrane receptors cloned from man."
PGRMC2:Hemes translocate to the nucleus
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PGRMC2 binds heme reversibly and can bind AAAS for nuclear import of heme complex.
"PGRMC2 binds heme reversibly. Also, PGRMC2 can bind to AAAS, a subunit of the nuclear pore complex, suggesting nuclear import of the PGRMC2:heme complex through the NPC takes place"
PGRMC2 binds Hemes
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PGRMC1 transfers heme to PGRMC2, which delivers heme to ER and nuclear proteins including Rev-Erba.
"Mitochondria-bound PGRMC1 transfers heme to ER-bound PGRMC2, which delivers heme to proteins in the ER and nucleus, including heme-responsive transcription factors such as Rev-Erbα"
PGRMC2:Hemes dissociates
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Heme dissociates from PGRMC2 in the nucleus.
"Free heme behaves differently in the nucleus, in the absence of PGRMC2. This implies that heme may separate from the PGRMC2:heme complex."
Deep research on PGRMC2 function
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PGRMC2 is an intracellular heme chaperone that delivers labile heme to the nucleus, regulating heme-responsive transcription factors.
"Initially characterized as a potential progesterone receptor due to nomenclature and early biochemical observations, PGRMC2 has emerged through recent research as a sophisticated intracellular heme chaperone and steroid hormone mediator whose primary function involves the highly regulated trafficking of labile heme from mitochondrial synthesis sites to nuclear and cytoplasmic target proteins."
Deep research on PGRMC2 function (falcon/Edison)
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MAPR/PGRMC2 is a cytochrome b5-like heme/steroid-binding domain protein distinct from PAQR/mPR 7TM membrane progesterone receptors; progesterone binding evidence is weaker for non-PGRMC1 MAPRs.
"MAPR proteins are often discussed as "non-classical" membrane progesterone receptors. However, mechanistic certainty varies by paralog. Reviews note that spectroscopic progesterone binding is established for PGRMC1, while progesterone binding "is still not proven for other MAPRs"—a caution that applies to PGRMC2."
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Recent functional evidence implicates PGRMC2 in immune homeostasis at the maternal-fetal interface, ciliogenesis/proliferation control, and endometrial epithelial proliferation, but cautions against assigning PGRMC2 a universal heme-allocation role for ER cytochromes P450.
"The 2024 JBC study showing no effect of strong PGRMC2 knockdown on heme insertion into CYP3A4/2D6 suggests either: PGRMC2 is not required for this heme allocation pathway, or its role is context-specific (cell type, client hemeprotein class, or redundancy with other heme chaperones). This kind of "negative result" is practically important for functional annotation: it constrains hypotheses that broadly assign PGRMC2 as a universal heme delivery factor for ER CYPs."
Functional maturation of cytochromes P450 3A4 and 2D6 relies on GAPDH- and Hsp90-Dependent heme allocation.
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PGRMC2 knockdown by ~80-85% in HEK293T cells did not impair mitochondrial 14C-heme allocation to ER-localized CYP3A4 or CYP2D6, arguing PGRMC2 is not a general heme chaperone for ER CYPs.
"The siRNA treatment caused 80 to 85% loss in PGRMC2 expression in the cells but this had no impact on CYP protein expression level (Fig. 8, A and B) or on the level of CYP 14C-heme incorporation (Fig. 8C). Thus, PGRMC2 is not likely to be involved in mitochondrial heme allocation to CYP3A4 or 2D6 in our system."
PGRMC2 and HLA-G regulate immune homeostasis in a microphysiological model of human maternal-fetal membrane interface.
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CRISPR/Cas9 PGRMC2 knockout in immortalized human chorion trophoblast cells disrupts immune homeostasis at the chorio-decidual interface; PGRMC2 acts upstream of HLA-G expression, restrains inflammation, and modulates mesenchymal-epithelial transition.
"HLA-G and PGRMC2 are found to be vital to immune homeostasis at the CDi, with PGRMC2 serving as an upstream regulator of inflammation, HLA-G expression, and mesenchymal-epithelial transition, and HLA-G serving as a frontline"
Identifying the roles of miR-17 in ciliogenesis and cell cycle.
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PGRMC2 was identified by ciliary proteomics as a membrane protein localized to the primary cilium in porcine LL-CPK1 epithelial cells; PGRMC2 knockdown reduced cilia number and length and produced a hyperproliferative phenotype. Direct evidence is in a non-human system; relevance to human PGRMC2 is by inference.
"Using unbiased proteomic studies, we most recently discovered five new membrane proteins localized in the cilia: bone morphogenetic type 2 (BMPR2), transferrin receptor-1 (TfR1), junctional adhesion molecule-A (JAM-A), protein tyrosine phosphatase receptor sigma (PTPRS), and progesterone receptor membrane component-2 (PGRMC2)"
PGRMC2 influences the onset of postmenopausal osteoporosis through disulfidptosis in monocytes: evidence from experimental validation and Mendelian randomization.
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Bioinformatic and Mendelian randomization analyses associate PGRMC2 with postmenopausal osteoporosis risk (MR OR 0.6836, p=0.0048; ROC AUC 0.665); PGRMC2 protein is reduced in ovariectomized mouse bone.
"A 2024 study integrated bulk expression, single-cell data, and experimental validation, proposing PGRMC2 as a gene linked to postmenopausal osteoporosis mechanisms (via "disulfidptosis" in monocytes/macrophages)."
Uterine Pgrmc2 Deficiency Attenuates Endometrial Hyperplasia and Cancer and Prolongs Lifespan in a Pten Loss-of-Function-Induced Cancer Model.
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Conditional uterine Pgrmc2 ablation in mice attenuates Pten loss-of-function-induced endometrial hyperplasia and carcinoma and prolongs lifespan, in part by inhibiting glandular epithelial cell proliferation; consistent with a permissive role of PGRMC2 in endometrial epithelial proliferation.
"The ablation of Pgrmc2 clearly attenuated the incidence/development, progression, and aggressiveness of Pten loss-of-function-induced endometrial cancer by inhibiting endometrial glandular epithelial cell proliferation (Figure 6)."
Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions - Focus on Interactions with Cytochromes P450.
Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease.