PGRMC2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: PGRMC2 localization to the ER is well-supported by multiple lines of evidence. The deep research confirms PGRMC2 localizes primarily to the endoplasmic reticulum and nuclear envelope [PMID:27754849]. This IBA annotation is phylogenetically appropriate and consistent with experimental data. Reason: ER localization is a core feature of PGRMC2 function as a heme chaperone that receives heme from mitochondria-bound PGRMC1 and delivers it to the nucleus. Multiple experimental studies confirm this localization. Supporting Evidence: PMID:27754849 Visualising PGRMC2 in the cell using immunofluorescence and confocal microscopy has shown the presence of PGRMC2 at the central ER, and, interestingly, at the nuclear envelope and the perinuclear ER. file:human/PGRMC2/PGRMC2-deep-research-perplexity.md The protein localizes primarily to the endoplasmic reticulum (ER) and nuclear envelope, with additional reported localization to mitochondria-associated membranes (MAMs).
GO:0012505 endomembrane system	IBA GO_REF:0000033	ACCEPT	Summary: PGRMC2 is a single-pass transmembrane protein localized to ER and nuclear envelope, which are part of the endomembrane system. This IBA annotation is appropriately broad and phylogenetically supported. Reason: As a membrane protein of the ER and nuclear envelope, PGRMC2 is correctly annotated to endomembrane system. This is consistent with its function in heme trafficking between cellular compartments. Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md PGRMC2 appears to operate as the downstream component in a relay system where mitochondria-bound PGRMC1 first acquires heme from ferrochelatase at the mitochondrial outer membrane, then transfers this heme to PGRMC2 localized on the endoplasmic reticulum and nuclear envelope.
GO:0016020 membrane	IBA GO_REF:0000033	ACCEPT	Summary: PGRMC2 is a single-pass transmembrane protein. The membrane annotation is accurate but very general. Reason: UniProt confirms PGRMC2 has a transmembrane domain (residues 42-66). While this is a broad term, the IBA annotation is phylogenetically sound. Supporting Evidence: file:human/PGRMC2/PGRMC2-uniprot.txt TRANSMEM 42..66 /note="Helical"
GO:0005496 steroid binding	IEA GO_REF:0000120	MODIFY	Summary: The historical name "progesterone receptor membrane component" suggested steroid binding, but modern research shows PGRMC2 primarily binds heme, not progesterone. The deep research explicitly states this protein binds heme rather than progesterone with high affinity [PMID:28111073]. Reason: While PGRMC2 was initially characterized as a potential steroid receptor, current evidence strongly supports heme binding as its primary ligand interaction. The IEA annotation based on automated pipelines reflects outdated understanding. GO:0020037 (heme binding) is more accurate. Proposed replacements: heme binding Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md This protein's discovery that it binds heme rather than progesterone with high affinity fundamentally reframed our understanding of non-classical steroid signaling. PMID:28111073 our initial studies point to heme-related molecules as potential candidates to serve this function
GO:0005576 extracellular region	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt indicates PGRMC2 can be secreted, based on detection in urine [PMID:37453717]. However, this appears to be a minor localization rather than a primary functional site. Reason: The secreted form may represent a secondary localization. The primary function of PGRMC2 as a heme chaperone occurs intracellularly at the ER and nuclear envelope. Supporting Evidence: file:human/PGRMC2/PGRMC2-uniprot.txt Secreted {ECO:0000269\|PubMed:37453717}.
GO:0005635 nuclear envelope	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear envelope localization is well-supported by experimental evidence showing PGRMC2 co-localizes with nucleoporin ALADIN at the NPC [PMID:27754849]. This IEA annotation is consistent with experimental data. Reason: Nuclear envelope localization is central to PGRMC2 function in delivering heme to the nucleus. This is supported by both the ALADIN interaction studies and Reactome pathway data. Supporting Evidence: PMID:27754849 We detected that PGRMC2 co-localises with ALADIN and with different FG-repeat NUPs [...] to the nuclear envelope and the perinuclear ER.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate of IBA annotation. ER localization is experimentally confirmed [PMID:27754849]. Reason: ER localization is well-supported and represents a core site of PGRMC2 function in the heme trafficking pathway. Supporting Evidence: PMID:27754849 Visualising PGRMC2 in the cell using immunofluorescence and confocal microscopy has shown the presence of PGRMC2 at the central ER, and, interestingly, at the nuclear envelope and the perinuclear ER.
GO:0008289 lipid binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This IEA annotation is based on UniProt keyword mapping. While PGRMC2 has a cytochrome b5-like domain that could theoretically bind lipids, the primary demonstrated binding activity is heme binding. Reason: There is no direct experimental evidence for lipid binding by PGRMC2. The primary ligand is heme. This annotation appears to be based on domain predictions rather than functional characterization. Recent reviews of the MAPR family explicitly caution that direct ligand-binding evidence outside heme is weaker for non-PGRMC1 MAPRs. Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md PGRMC2 exhibits reversible heme binding characteristic of signaling proteins that require dynamic exchange of heme with other proteins. file:human/PGRMC2/PGRMC2-deep-research-falcon.md Reviews highlight that PGRMC2 is less well characterized than PGRMC1 (tissue specificity, interaction network, subcellular locations). Additionally, progesterone binding evidence is weaker for non-PGRMC1 MAPRs.
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate membrane annotation. PGRMC2 is a single-pass transmembrane protein. Reason: Membrane localization is well-established for this transmembrane protein. Supporting Evidence: file:human/PGRMC2/PGRMC2-uniprot.txt TRANSMEM 42..66 /note="Helical"
GO:0030518 nuclear receptor-mediated steroid hormone signaling pathway	IEA GO_REF:0000108	REMOVE	Summary: This annotation reflects the outdated view of PGRMC2 as a steroid receptor. Current evidence indicates PGRMC2 functions primarily as a heme chaperone, not a steroid receptor. Reason: The deep research clearly states that PGRMC2 binds heme rather than progesterone with high affinity. Its role in the nucleus involves delivering heme to transcription factors, not steroid hormone signaling. Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md 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.
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from high-throughput interactome study. While PGRMC2 does interact with proteins (PGRMC1, ALADIN), this term is uninformative. Reason: Protein binding is too generic. More specific interaction partners such as PGRMC1 and AAAS (ALADIN) are documented, but the generic protein binding term adds no information about function. Supporting Evidence: PMID:27173435 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
GO:0005515 protein binding	IPI PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ...	MARK AS OVER ANNOTATED	Summary: This paper focuses on PGRMC1 and ferrochelatase interaction, not PGRMC2 directly. PGRMC2 may be detected as part of the heme trafficking complex. Reason: Generic protein binding term. The paper title mentions PGRMC1, and PGRMC2 interaction may be indirect through the PGRMC1-PGRMC2 relay system. Supporting Evidence: PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase.
GO:0005515 protein binding	IPI PMID:29513927 Comparative Protein Interaction Network Analysis Identifies ...	MARK AS OVER ANNOTATED	Summary: High-throughput protein interaction study on ROCO proteins. Generic protein binding annotation. Reason: Generic protein binding from high-throughput study. Does not provide specific functional insight. Supporting Evidence: PMID:29513927 Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Large-scale binary protein interactome mapping. Generic annotation. Reason: Generic protein binding from high-throughput interactome study. 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: Proteome-scale network study. Generic protein binding annotation. Reason: Generic protein binding from high-throughput study. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous tagging study. Generic protein binding. Reason: Generic protein binding from high-throughput cellular cartography study. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:40355756 The solute carrier superfamily interactome.	MARK AS OVER ANNOTATED	Summary: Solute carrier superfamily interactome study. Generic protein binding. Reason: Generic protein binding from high-throughput interactome study. Supporting Evidence: PMID:40355756 The solute carrier superfamily interactome.
GO:0015232 heme transmembrane transporter activity	IEA GO_REF:0000107	MODIFY	Summary: This annotation suggests PGRMC2 actively transports heme across membranes. However, PGRMC2 is described as a heme chaperone that binds and delivers heme, not as a transmembrane transporter. Reason: PGRMC2 is a heme chaperone, not a heme transporter. It binds heme reversibly and delivers it to target proteins, but does not function as a transmembrane transporter. The correct term is heme binding. Proposed replacements: heme binding Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md This reversible binding capacity is essential to PGRMC2's proposed mechanism as a chaperone protein that accepts heme from one source (mitochondria-bound PGRMC1) and transfers it to target proteins in the nucleus and endoplasmic reticulum.
GO:0015886 heme transport	IEA GO_REF:0000107	ACCEPT	Summary: PGRMC2 does participate in intracellular heme trafficking as a chaperone, facilitating heme delivery from ER to nucleus. Note, however, that PGRMC2 is not universally required for heme delivery to all ER hemoproteins: siRNA knockdown of PGRMC2 in HEK293T cells did not impair mitochondrial heme allocation to ER-resident CYP3A4 or CYP2D6 [PMID:38199567], arguing for client-specific rather than bulk heme chaperone activity. Reason: While PGRMC2 is not a transporter in the classical sense, it does function in heme transport/trafficking by chaperoning heme to the nucleus. This broader process term is appropriate. Supporting Evidence: Reactome:R-HSA-9707606 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 (Jühlen et al, 2016; Parker et al, 2017; Galmozzi et al 2020). PMID:38199567 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.
GO:0020037 heme binding	IEA GO_REF:0000107	ACCEPT	Summary: Heme binding is the primary molecular function of PGRMC2. This is well-supported by experimental evidence [PMID:28111073] and is central to its function as a heme chaperone. Reason: Heme binding is the core molecular function of PGRMC2, confirmed by fragment-based screening in human cells and functional studies. Supporting Evidence: PMID:28111073 our initial studies point to heme-related molecules as potential candidates to serve this function file:human/PGRMC2/PGRMC2-deep-research-perplexity.md Unlike constitutive heme-binding proteins such as myoglobin and hemoglobin, which maintain essentially irreversible heme binding through multiple coordination interactions, PGRMC2 exhibits reversible heme binding characteristic of signaling proteins.
GO:0045202 synapse	IEA GO_REF:0000107	UNDECIDED	Summary: No evidence for synaptic localization or function in the deep research or UniProt entry for PGRMC2. Reason: Unable to find supporting evidence for synaptic localization. This may be transferred from ortholog data that needs verification. Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md The protein localizes primarily to the endoplasmic reticulum (ER) and nuclear envelope.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	UNDECIDED	Summary: No evidence for glutamatergic synapse localization in the available literature for PGRMC2. Reason: This appears to be transferred from ortholog data. No direct evidence supports glutamatergic synapse localization for human PGRMC2. Supporting Evidence: file:human/PGRMC2/PGRMC2-deep-research-perplexity.md PGRMC2 expression is most abundant in placenta, followed by significant expression in adipose tissue, reproductive organs, heart, and gastrointestinal tissues.
GO:0005635 nuclear envelope	TAS Reactome:R-HSA-9707606	ACCEPT	Summary: Reactome pathway shows PGRMC2:heme complex translocates to nucleus via interaction with AAAS at the NPC. Reason: Nuclear envelope localization is essential for PGRMC2 function in delivering heme to nuclear targets. Well-supported by Reactome curation. Supporting Evidence: Reactome:R-HSA-9707606 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
GO:0005635 nuclear envelope	TAS Reactome:R-HSA-9707683	ACCEPT	Summary: Duplicate nuclear envelope annotation from Reactome heme binding pathway. Reason: Nuclear envelope localization is well-supported and central to PGRMC2 function in heme delivery. Supporting Evidence: Reactome:R-HSA-9707683 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
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9707606	ACCEPT	Summary: PGRMC2 delivers heme to the nucleus, and the heme:PGRMC2 complex may transiently enter the nucleoplasm before dissociation. Reason: Nucleoplasm localization is consistent with PGRMC2 function in delivering heme to nuclear transcription factors. Supporting Evidence: Reactome:R-HSA-9707856 Free heme behaves differently in the nucleus, in the absence of PGRMC2. This implies that heme may separate from the PGRMC2:heme complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9707856	ACCEPT	Summary: Duplicate nucleoplasm annotation from Reactome heme dissociation pathway. Reason: Nucleoplasm localization is supported by Reactome curation of heme signaling pathway. Supporting Evidence: Reactome:R-HSA-9707856 Free heme behaves differently in the nucleus, in the absence of PGRMC2.
GO:0005515 protein binding	IPI PMID:27754849 Identification of a novel putative interaction partner of th...	KEEP AS NON CORE	Summary: This study specifically identified PGRMC2 interaction with ALADIN (AAAS), a nucleoporin. While the generic protein binding term is used, this paper provides important functional context. Reason: The interaction with ALADIN is functionally significant for nuclear heme delivery. However, protein binding is still a generic term. Supporting Evidence: PMID:27754849 Our results suggest an interaction of ALADIN with the microsomal protein PGRMC2.
GO:0005635 nuclear envelope	IDA PMID:27754849 Identification of a novel putative interaction partner of th...	ACCEPT	Summary: Direct experimental evidence for nuclear envelope localization using immunofluorescence and confocal microscopy. Reason: Strong experimental evidence from direct visualization showing PGRMC2 co-localizes with ALADIN and NPC proteins at the nuclear envelope. Supporting Evidence: PMID:27754849 We detected that PGRMC2 co-localises with ALADIN and with different FG-repeat NUPs [...] to the nuclear envelope and the perinuclear ER.
GO:0005635 nuclear envelope	IDA PMID:28111073 Ligand and Target Discovery by Fragment-Based Screening in H...	ACCEPT	Summary: Fragment-based screening study that characterized PGRMC2 localization and heme binding. Reason: This study provided key evidence for PGRMC2 as a heme-binding protein involved in adipocyte differentiation and nuclear heme delivery. Supporting Evidence: PMID:28111073 We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2.
GO:0005783 endoplasmic reticulum	IDA PMID:27754849 Identification of a novel putative interaction partner of th...	ACCEPT	Summary: Direct experimental evidence for ER localization from immunofluorescence studies. Reason: ER localization is experimentally confirmed and central to PGRMC2 function in the heme trafficking pathway. Supporting Evidence: PMID:27754849 Visualising PGRMC2 in the cell using immunofluorescence and confocal microscopy has shown the presence of PGRMC2 at the central ER, and, interestingly, at the nuclear envelope and the perinuclear ER.
GO:0020037 heme binding	IDA PMID:28111073 Ligand and Target Discovery by Fragment-Based Screening in H...	ACCEPT	Summary: Direct experimental evidence for heme binding from fragment-based screening and functional studies in human cells. Reason: Heme binding is the core molecular function of PGRMC2. This study provided key evidence identifying heme-related molecules as PGRMC2 ligands. Supporting Evidence: PMID:28111073 our initial studies point to heme-related molecules as potential candidates to serve this function
GO:0060612 adipose tissue development	IMP PMID:28111073 Ligand and Target Discovery by Fragment-Based Screening in H...	KEEP AS NON CORE	Summary: Functional studies showed PGRMC2 regulates adipocyte differentiation. Deep research confirms PGRMC2 role in brown adipose tissue thermogenesis and adipogenesis. Reason: PGRMC2 plays important roles in adipose tissue function and development, particularly in brown adipose tissue thermogenesis. This is a downstream physiological consequence of the molecular heme-chaperone role; recent work also highlights tissue-specific PGRMC2 functions at the maternal- fetal interface, ciliogenesis/proliferation, and endometrial epithelial proliferation that are not adipose-related, supporting that adipose development is a non-core pleiotropic process. Supporting Evidence: PMID:28111073 identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2 file:human/PGRMC2/PGRMC2-deep-research-perplexity.md Among PGRMC2's most thoroughly characterized physiological functions is its role in regulating brown adipocyte metabolism and thermogenesis.
GO:0005635 nuclear envelope	IDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	ACCEPT	Summary: This paper is about E-cadherin interactome proteomics. PGRMC2 was identified in proximity biotinylation, which does not directly support nuclear envelope localization. Reason: While this specific paper used proximity proteomics and may not directly demonstrate nuclear envelope localization, other evidence strongly supports this localization for PGRMC2. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: High-throughput membrane proteomics study of NK cells identified PGRMC2 as a membrane protein. Reason: PGRMC2 is a single-pass transmembrane protein, consistent with identification in membrane proteome. Supporting Evidence: PMID:19946888 The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS.
GO:0003707 nuclear steroid receptor activity	TAS PMID:9705155 Cloning and tissue expression of two putative steroid membra...	REMOVE	Summary: This 1998 paper described initial cloning of PGRMC2 (called Dg6) as a putative steroid membrane receptor. However, subsequent research has shown PGRMC2 is primarily a heme chaperone, not a steroid receptor. Reason: Modern research has definitively shown PGRMC2 binds heme, not progesterone with high affinity. This annotation reflects outdated understanding from the original cloning paper. Supporting Evidence: PMID:9705155 The two proteins are the first putative steroid membrane receptors cloned from man. file:human/PGRMC2/PGRMC2-deep-research-perplexity.md 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.
GO:0005496 steroid binding	TAS PMID:9705155 Cloning and tissue expression of two putative steroid membra...	MODIFY	Summary: Based on original 1998 cloning paper when PGRMC2 was thought to be a steroid receptor. This is now known to be incorrect. Reason: PGRMC2 binds heme, not steroids, with high affinity. The correct molecular function term is heme binding. Proposed replacements: heme binding Supporting Evidence: PMID:9705155 Both proteins contain a putative transmembrane domain and a highly conserved stretch of 58 amino acids. file:human/PGRMC2/PGRMC2-deep-research-perplexity.md This protein's discovery that it binds heme rather than progesterone with high affinity fundamentally reframed our understanding of non-classical steroid signaling.
GO:0016020 membrane	TAS PMID:9705155 Cloning and tissue expression of two putative steroid membra...	ACCEPT	Summary: Original cloning paper correctly identified PGRMC2 as a membrane protein. Reason: PGRMC2 is a single-pass transmembrane protein. This aspect of the original characterization remains accurate. Supporting Evidence: PMID:9705155 Both proteins contain a putative transmembrane domain and a highly conserved stretch of 58 amino acids.

Gene Description

Existing Annotations Review

Core Functions

PGRMC2 functions as a reversible heme-binding protein that receives heme from PGRMC1 at the ER and delivers it to the nucleus, where it regulates heme-responsive transcription factors such as Rev-Erba and BACH1.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Perplexity

📄 View Raw YAML