PGRMC1 (Progesterone Receptor Membrane Component 1; also known as Sigma-2 receptor complex member, mPR, Hpr6.6, Dap1, IZA) is a ~195-aa single-pass tail-anchored membrane protein of the MAPR (Membrane-Associated Progesterone Receptor) subfamily of the cytochrome b5 superfamily. Its primary, evolutionarily conserved molecular function is binding of heme B via an atypical pentacoordinate Tyr113 axial ligand in a surface-exposed pocket of its cytochrome b5-like cytosolic domain; heme binding drives reversible dimerization through heme-heme stacking (with additional Cys129-mediated disulfide oligomerization contributing in vitro). PGRMC1 is predominantly an endoplasmic reticulum (ER) membrane protein but is also present at the plasma membrane, nuclear/perinuclear membranes, endosomes, Golgi and the outer mitochondrial membrane in a cell-type- and context-dependent manner. Its best-supported biological role is as a heme-dependent regulator of microsomal cytochrome P450 (CYP) enzyme systems: it physically interacts with multiple CYPs (including CYP51A1, CYP21A2, CYP7A1, CYP3A4, CYP2C8, CYP2C2, CYP1A2) and with cytochrome P450 reductase (CPR), modulating CYP activity in an isoform-dependent manner — stimulating sterol-biosynthetic CYPs (notably CYP51A1) while inhibiting several drug-metabolising CYPs. Through ferrochelatase (FECH) binding and apo-cytochrome b5 heme transfer in vitro, PGRMC1 has been implicated in heme trafficking/buffering. PGRMC1 also participates in cell-surface complexes that pleiotropically influence ligand uptake and signalling, including the TMEM97 (sigma-2 receptor)/PGRMC1/LDLR ternary complex that accelerates LDL internalization, and a synaptic complex implicated in amyloid-beta oligomer binding in Alzheimer's disease. The "progesterone receptor" name is historical; contemporary expert reviews frame PGRMC1 as a membrane heme-binding regulator rather than as a classical ligand-activated progesterone receptor.
Definition: A molecular function describing physical, heme-dependent binding to cytochrome P450 enzymes that modulates (positively or negatively, in an isoform-specific manner) their catalytic activity without electron transfer. Distinguishes the MAPR-family role (haem-dependent allosteric modulator) from electron-donating partners of CYPs (cytochrome b5 and cytochrome P450 reductase).
Justification: PGRMC1 (and the MAPR family generally) acts as a haem-dependent regulator of microsomal CYPs, distinct from cytochrome b5 (electron donor) and CPR (electron donor). Existing GO terms such as GO:0008047 (enzyme activator activity) do not capture the haem-dependent, isoform-specific, bidirectional (activator/inhibitor) CYP-modulating role of PGRMC1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localisation is the single most consistently reported subcellular site for PGRMC1 across cell types and is supported by the falcon review, the perplexity review, and primary biochemical/microscopy studies. The IBA call is consistent with experimentally documented ER residence. Reason: PGRMC1 is a tail-anchored ER membrane MAPR-family protein; ER residence is a core, conserved localisation that underlies its interactions with ER-resident CYPs and the heme synthesis/trafficking machinery. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md PGRMC1 localization is repeatedly reported as **context-dependent**, with strong recurring evidence for association with the **endoplasmic reticulum (ER)/endomembranes** PMID:21081644 In most cells, PGRMC1 is localized in the membranes of the ER |
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Endomembrane system is a broad parent term encompassing ER, Golgi, endosomes and plasma membrane. PGRMC1 is documented at multiple endomembrane sites, but more specific terms (endoplasmic reticulum, plasma membrane, smooth ER membrane) capture its biology more informatively. Reason: Redundant with the more informative GO:0005783 endoplasmic reticulum annotation already present; "endomembrane system" is too generic to convey meaningful localisation information. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md additional reported localization to the **plasma membrane**, **nucleus/nuclear membrane**, **Golgi**, **endosomes**, **cytoplasm**, and **mitochondria** depending on cell type and condition. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: "membrane" is the most generic possible cellular component term. PGRMC1 is unambiguously a single-pass membrane protein, but ER membrane / smooth ER membrane / plasma membrane are the informative annotations to retain. Reason: Uninformative parent term; superseded by the specific ER and plasma membrane annotations already present. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md Human **PGRMC1 (O00264)** is a **single-pass membrane MAPR protein** |
| GO:0005496 steroid binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Direct steroid (progesterone) binding by PGRMC1 is historically asserted (the gene was named for it) but the evidence is equivocal: some purified-protein studies report progesterone binding requiring the transmembrane region while recombinant truncated cytosolic domain assays have failed to detect direct binding. Contemporary expert syntheses (falcon, 2024) frame PGRMC1 as a heme- binding MAPR protein rather than a classical progesterone receptor. Keeping as non-core captures historical/possible function without elevating it to the core molecular activity. Reason: Evidence for direct, high-affinity steroid binding by PGRMC1 alone is weak and disputed; the heme-binding role is the unambiguously supported core molecular function. Retain for completeness but not as a core activity. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md Current expert reviews frame PGRMC1 less as a simple on/off “progesterone receptor” and more as a **membrane-associated heme-binding regulator** |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | REMOVE | Summary: PGRMC1 is a membrane-anchored protein with no characterised secreted form. The annotation likely originates from automated SwissProt subcellular-location mapping that registered "secretory granule membrane" type annotations as extracellular region. There is no evidence in the falcon, perplexity, or primary literature for genuine extracellular soluble PGRMC1. Reason: No biological evidence supports a free extracellular pool of PGRMC1; the protein is membrane-anchored throughout its life cycle. Annotation appears to be a SwissProt-keyword automation artefact. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md Human **PGRMC1 (O00264)** is a **single-pass membrane MAPR protein** |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: A pool of PGRMC1 is found on the cytosolic (outer) face of the outer mitochondrial membrane, where it interacts with the ferrochelatase-containing heme metabolon. This is experimentally supported by proteinase-protection fractionation in MEL cells (Piel et al. 2016). Reason: PGRMC1 outer mitochondrial membrane localisation is genuine but represents a minor subcellular pool relevant to its heme-trafficking/FECH-interaction role, not its core ER residence. Supporting Evidence: PMID:27599036 Further experiments to characterize the sub-mitochondrial localization were consistent with the majority of PGRMC1 being on the outside of the outer mitochondrial membrane. |
| GO:0008289 lipid binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Generic "lipid binding" is too broad and not the established core activity. PGRMC1 binds heme (a tetrapyrrole, not a lipid in the typical GO sense) and possibly steroids; sterol binding/transfer activity has been proposed but not biochemically demonstrated for purified PGRMC1. Reason: Uninformative; specific molecular function GO:0020037 (heme binding) and GO:0005496 (steroid binding) are already annotated. No published evidence for general phospholipid binding. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md Most defensible primary functional description (integrating 2023–2024 evidence):** Human **PGRMC1 (O00264)** is a **single-pass membrane MAPR protein** with a **cytochrome b5-like heme-binding domain** |
| GO:0030868 smooth endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: PGRMC1 is enriched in microsomal (smooth ER) fractions, consistent with its co-localisation and interaction with smooth-ER-resident cytochrome P450 enzymes. This is a more informative refinement of the parent GO:0005783 annotation. Reason: Smooth ER membrane is the precise compartment for PGRMC1's interactions with microsomal CYP enzymes; well supported by microsomal fractionation studies. Supporting Evidence: PMID:21081644 PGRMC1 is a small 25-kDa protein with an N-terminal membrane binding segment and a C-terminal domain with a cytochrome b 5 -like structure that binds heme. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: PGRMC1 binds iron via the heme cofactor (pentacoordinate Tyr113 coordination of haem iron). Annotation as "metal ion binding" is technically correct via the bound heme but is uninformative; "heme binding" (GO:0020037) is the appropriate specific term and is already annotated. Reason: Redundant with and less informative than the heme binding annotations; PGRMC1 does not coordinate free metal ions directly. Supporting Evidence: PMID:26988023 the haem iron is five-coordinated by Tyr113 (Y113) alone |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | MARK AS OVER ANNOTATED | Summary: Generic IPI "protein binding" annotation from a high-throughput mass-spec interactome screen. Not informative about PGRMC1's specific molecular function. Specific functional protein interactions (with CYPs, CPR, FECH, EGFR, TMEM97, LDLR) are captured by more meaningful annotations. Reason: Per GO curation guidelines, generic "protein binding" should be avoided when more informative MF terms exist or when the partner is not specified. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry. |
| GO:0005515 protein binding | IPI PMID:21081644 Progesterone receptor membrane component 1 inhibits the acti... | MARK AS OVER ANNOTATED | Summary: Captures PGRMC1's documented direct interactions with multiple drug- metabolising P450s (CYP2C2, CYP2C8, CYP3A4) and cytochrome P450 reductase (CPR), but "protein binding" itself is uninformative. The functional consequence (modulation of P450 activity) is the core finding. Reason: Use specific molecular-function terms (heme binding, and a process term for cytochrome P450 modulation) rather than generic protein binding. Supporting Evidence: PMID:21081644 PGRMC1 bound efficiently to all three P450s PMID:21081644 In cells cotransfected with CPR and PGRMC1, strong binding of CPR to PGRMC1 was observed |
| GO:0005515 protein binding | IPI PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | MARK AS OVER ANNOTATED | Summary: Reflects the experimentally validated direct interaction of PGRMC1 with ferrochelatase (FECH). The interaction is informative and functional but the generic GO:0005515 term itself is not. Reason: Specific interaction with FECH is functionally informative but should not be captured as the generic protein-binding term; the process-level role (heme biosynthesis/regulation of FECH) is the appropriate annotation. Supporting Evidence: PMID:27599036 The interaction between PGRMC1 and FECH was confirmed in vitro and in HEK 293T cells |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome screen; generic protein binding annotation. Reason: Per GO guidelines, generic protein binding is uninformative and the interactome studies do not specify functional consequences. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | MARK AS OVER ANNOTATED | Summary: Histone crosslinking mass-spec study; PGRMC1's apparent association with histones in intact nuclei is a peripheral context not part of its core biology and the generic protein-binding term is uninformative. Reason: Generic IPI from a high-throughput crosslinking study; nuclear/chromatin proximity is consistent with reported nuclear/nucleolar pools but not core function. Supporting Evidence: PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic IPI from a Y2H-based reference binary interactome map. Provides no specific functional information. Reason: Uninformative high-throughput protein binding call. 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: Generic IPI from BioPlex/AP-MS proteome-scale network. Reason: Uninformative high-throughput protein binding call. 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: Generic IPI from OpenCell endogenous-tagging cartography of human protein complexes; not functionally informative on its own. Reason: Uninformative high-throughput protein binding call. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Generic IPI from a multimodal cell map; not informative about specific function or partner. Reason: Uninformative high-throughput protein binding call. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0007411 axon guidance | IEA GO_REF:0000107 | REMOVE | Summary: Inferred by automatic Ensembl Compara orthology transfer (GO_REF:0000107). There is no direct experimental evidence for PGRMC1 functioning in axon guidance in human; the falcon synthesis does not mention this role. Likely spurious ortholog-based transfer. Reason: No direct evidence for an axon-guidance function of PGRMC1 in any model organism; orthology-based IEA is not adequately supported. Supporting Evidence: file:human/PGRMC1/PGRMC1-deep-research-falcon.md Most defensible primary functional description |
| GO:0007613 memory | IEA GO_REF:0000107 | REMOVE | Summary: Automatic ortholog-based IEA. While PGRMC1 has been linked to Alzheimer's disease through Abeta oligomer binding, "memory" as a direct biological process annotation is too broad and not directly supported by experimental evidence for human PGRMC1. The synaptic effects are downstream/disease-context rather than a core gene function. Reason: Phenotype-level term, not a molecular function/process directly executed by PGRMC1; ortholog-based transfer is weak. |
| GO:0008306 associative learning | IEA GO_REF:0000107 | REMOVE | Summary: Automatic ortholog-based IEA. Same reasoning as for memory and axon guidance: no direct experimental evidence and these are phenotype-level terms rather than core PGRMC1 functions. Reason: Phenotype-level term not directly supported by experimental evidence for PGRMC1. |
| GO:0020037 heme binding | IEA GO_REF:0000107 | ACCEPT | Summary: Heme binding is the core, evolutionarily conserved molecular function of PGRMC1 and is supported by extensive crystallographic, spectroscopic, biochemical and mutagenesis evidence (Tyr113 axial coordination, ~50 nM Kd, heme-dependent dimerisation). This is the single most important MF term. Reason: Core molecular function backed by multiple lines of high-quality evidence. Supporting Evidence: PMID:26988023 the haem iron is five-coordinated by Tyr113 (Y113) alone file:human/PGRMC1/PGRMC1-deep-research-falcon.md Multiple lines of evidence support that **PGRMC1 binds heme** at a **surface-exposed site**. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PGRMC1 is broadly expressed including in neurons and has been detected in post-synaptic compartments; presence in neuronal projections is consistent with the Abeta-binding / synaptic localisation literature. Annotation is plausible but is not a core function. Reason: Cellular-component term reflecting neuronal expression context, not a core PGRMC1 function. Supported by immunofluorescence studies of synaptic puncta. Supporting Evidence: PMID:25390692 sigma-2/PGRMC1 is expressed at low levels in cell bodies of neurons and glia, and in proximal neurites |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Same rationale as neuron projection - PGRMC1 is detected in neuronal cell bodies (immunofluorescence in cultured hippocampal/cortical neurons), but this is an expression-context CC term not a core function. Reason: Reflects neuronal expression, not a core mechanistic function. Supporting Evidence: PMID:25390692 sigma-2/PGRMC1 is expressed at low levels in cell bodies of neurons and glia |
| GO:0044297 cell body | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Parent term of neuronal cell body; uninformative. Reason: Redundant with the more specific GO:0043025 (neuronal cell body) annotation. |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Sigma-2/PGRMC1 is enriched in post-synaptic density fractions of rat brain and detected at synaptic puncta in cultured neurons; this synaptic pool underlies its proposed role as a receptor/binding site for Abeta oligomers. Plausible non-core localisation. Reason: Synaptic localisation is documented in brain but is a tissue/context-specific pool, not the core ER-centric localisation of PGRMC1. Supporting Evidence: PMID:25390692 PGRMC1 is widely expressed in brain at low levels, where it is enriched in the post-synaptic density fraction |
| GO:0099563 modification of synaptic structure | IEA GO_REF:0000107 | REMOVE | Summary: Ortholog-based IEA. Some literature links sigma-2/PGRMC1 ligands to changes in synaptic membrane trafficking and reversible spine loss in Abeta-treated neurons, but direct evidence that PGRMC1 itself executes a "modification of synaptic structure" molecular role is weak. Reason: Process is downstream/context-dependent (Abeta oligomer signalling) rather than an autonomous PGRMC1 process. Ortholog-based IEA is not adequate support. |
| GO:1905809 negative regulation of synapse organization | IEA GO_REF:0000107 | REMOVE | Summary: Ortholog-based IEA. Same rationale as for "modification of synaptic structure"; not core PGRMC1 biology. Reason: Phenotype-/context-level process not directly executed by PGRMC1; weak IEA evidence. |
| GO:0005515 protein binding | IPI PMID:37047353 Sigma-2 Receptor Ligand Binding Modulates Association betwee... | MARK AS OVER ANNOTATED | Summary: Reflects PGRMC1 co-immunoprecipitation with TSPO in MIA PaCa-2 cells, in the context of TSPO/TMEM97/sigma-2 receptor complex biology. The functional meaning of the binding is debated and cell-type-dependent. Generic protein binding is uninformative. Reason: Specific cell-context interaction with TSPO is interesting but generic protein-binding is uninformative; the relevant biology is the PGRMC1/TMEM97 sigma-2 complex. Supporting Evidence: PMID:37047353 in MP cells, we observed that both TMEM97 (Figure 4C) and PGRMC1 (Figure 4D) co-immunoprecipitated with TSPO |
| GO:0005515 protein binding | IPI PMID:30443021 Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Int... | MARK AS OVER ANNOTATED | Summary: Reflects PGRMC1 in the TMEM97(sigma-2)/PGRMC1/LDLR ternary complex that accelerates LDL internalisation. The specific functional interaction is important and is captured by the related process annotation GO:0140077 (positive regulation of lipoprotein transport). Reason: Generic protein binding is uninformative; the functional consequence (LDLR/TMEM97 complex / LDL uptake) is captured elsewhere. Supporting Evidence: PMID:30443021 These data indicate that the formation of a ternary complex of LDLR-PGRMC1-TMEM97 is necessary for the rapid internalization of LDL by LDLR. |
| GO:0140077 positive regulation of lipoprotein transport | IMP PMID:30443021 Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Int... | KEEP AS NON CORE | Summary: CRISPR knockout of PGRMC1 in HeLa cells significantly reduced uptake of radiolabelled or fluorescently tagged LDL via the LDL receptor; the LDLR/TMEM97/PGRMC1 ternary complex is required for rapid LDL internalisation. This is a directly experimentally supported process role, although it represents one of several pleiotropic functions and is not the deepest core function. Reason: Genuine, well-supported PGRMC1 function but it acts in concert with TMEM97/LDLR in a specific membrane complex; this is one of multiple pleiotropic roles rather than the gene's primary molecular activity. Supporting Evidence: PMID:30443021 Uptake of radiolabeled LDL was significantly decreased in PGRMC1 KO, TMEM97 KO, and double KO cell lines. PMID:30443021 These data indicate that the formation of a ternary complex of LDLR-PGRMC1-TMEM97 is necessary for the rapid internalization of LDL by LDLR. |
| GO:0005886 plasma membrane | TAS PMID:25390692 Alzheimer's therapeutics targeting amyloid beta 1-42 oligome... | ACCEPT | Summary: A pool of PGRMC1 (often referred to as cell-surface PGRMC1 or csPGRMC1) translocates to the plasma membrane in many cell types and is the site at which the TMEM97/PGRMC1/LDLR ternary complex and the proposed sigma-2/PGRMC1 Abeta-oligomer binding occur. Well supported by multiple cell biology studies. Reason: Plasma membrane localisation is a genuine, functionally important pool of PGRMC1 supported by multiple lines of evidence. Supporting Evidence: PMID:25390692 translocates from the endoplasmic reticulum to the plasma membrane in several cell types |
| GO:0020037 heme binding | TAS PMID:25390692 Alzheimer's therapeutics targeting amyloid beta 1-42 oligome... | ACCEPT | Summary: Heme binding is the core molecular function of PGRMC1; multiple lines of evidence (review citation here, plus IDA direct binding studies). Reason: Core, well-supported molecular function. Supporting Evidence: PMID:25390692 PGRMC1 is a highly conserved heme-binding protein in the membrane associated progesterone receptor (MAPR) family |
| GO:0043005 neuron projection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Same as the IEA call above - neuronal/dendritic localisation reflects expression context not core function. Reason: Tissue-expression context, not core PGRMC1 mechanism. Supporting Evidence: PMID:25390692 sigma-2/PGRMC1 is expressed at low levels in cell bodies of neurons and glia, and in proximal neurites |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: As for the IEA call above. Reason: Tissue-expression context, not core PGRMC1 mechanism. Supporting Evidence: PMID:25390692 sigma-2/PGRMC1 is expressed at low levels in cell bodies of neurons and glia |
| GO:0045202 synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: As for the IEA call above. Reason: Synaptic pool documented in brain; non-core context. Supporting Evidence: PMID:25390692 PGRMC1 is widely expressed in brain at low levels, where it is enriched in the post-synaptic density fraction |
| GO:1903078 positive regulation of protein localization to plasma membrane | IMP PMID:25390692 Alzheimer's therapeutics targeting amyloid beta 1-42 oligome... | KEEP AS NON CORE | Summary: PGRMC1 has been shown to stabilise plasma membrane levels of EGFR and (in adipocyte models) of LDL-R, VLDL-R and GLUT4 via heme-dependent dimerisation. Genuine but pleiotropic function. Reason: Membrane-receptor trafficking effects are well documented for several partners (EGFR, LDL-R/VLDL-R, GLUT4) and are biologically significant, but represent context-dependent applications of PGRMC1's core membrane-protein- adaptor activity rather than its core mechanism. Supporting Evidence: PMID:25390692 PGRMC1 is a highly conserved heme-binding protein in the membrane associated progesterone receptor (MAPR) family that has been shown to stabilize surface receptor expression of proteins and directly associates with proteins that regulate membrane trafficking |
| GO:0005515 protein binding | IPI PMID:26988023 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facil... | MARK AS OVER ANNOTATED | Summary: Captures the well-characterised haem-dependent binding of PGRMC1 to EGFR and to cytochromes P450 (CYP1A2, CYP3A4, CYP51), but the generic term itself is uninformative; the functional consequence (P450 modulation, EGFR signalling) is the meaningful annotation. Reason: Specific, functional partner interactions should be captured by process annotations; generic protein binding is uninformative. Supporting Evidence: PMID:26988023 Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450 |
| GO:0020037 heme binding | IDA PMID:26988023 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facil... | ACCEPT | Summary: Direct assay (X-ray crystallography at 1.95 Å, NMR, MS, SV-AUC, UV-vis, resonance Raman, ITC) of heme binding by PGRMC1 cytosolic domain. Kd ~50 nM. This is the highest-quality experimental support for the core heme-binding function. Reason: Direct biochemical and structural evidence for core MF. Supporting Evidence: PMID:26988023 haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1 PMID:26988023 the haem iron is five-coordinated by Tyr113 (Y113) alone |
| GO:0042803 protein homodimerization activity | IDA PMID:26988023 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facil... | ACCEPT | Summary: PGRMC1 homodimerises via two non-mutually-exclusive mechanisms: heme-heme stacking between two protruding haem moieties and intermolecular Cys129-Cys129 disulfide bonding. The functional dimer is required for EGFR and CYP interactions and for cancer cell proliferation. Reason: Well-supported direct molecular function; the heme-dependent dimer is a regulatory/functional state. Supporting Evidence: PMID:26988023 PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers PMID:26988023 the apo-monomer PGRMC1 resulted in dimerization by binding with haem |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Same as the IEA outer mitochondrial membrane annotation - a real but minor pool of PGRMC1. Reason: Minor functional pool relevant to FECH interaction / heme trafficking. Supporting Evidence: PMID:27599036 Further experiments to characterize the sub-mitochondrial localization were consistent with the majority of PGRMC1 being on the outside of the outer mitochondrial membrane. |
| GO:0006783 heme biosynthetic process | IDA PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | ACCEPT | Summary: PGRMC1 interacts with ferrochelatase (FECH) and inhibits FECH activity in vitro in a dose-dependent manner; AG-205 PGRMC1 inhibitor treatment reduces hemoglobinisation in differentiating MEL cells. PGRMC1 also donates heme to apo-cytochrome b5 in vitro. PGRMC1 is therefore implicated as a regulator of heme biosynthesis, although its precise role (inhibitor vs. chaperone vs. product-release regulator) is not fully resolved. Reason: Direct experimental evidence supports PGRMC1 involvement in heme synthesis regulation via FECH. Although the directionality of regulation is complex (it inhibits FECH in vitro yet AG-205 treatment reduces hemoglobinisation), the process-level annotation is appropriate. Supporting Evidence: PMID:27599036 In the presence of PGRMC1, in vitro measured FECH activity decreased in a dose-dependent manner. PMID:27599036 When cells that are recognized models for erythroid differentiation were treated with a small molecule inhibitor of PGRMC1, AG-205, there was an observed decrease in the level of hemoglobinization relative to that of untreated cells. PMID:27599036 In vitro heme transfer experiments showed that purified PGRMC1 was able to donate heme to apo-cytochrome b5. |
| GO:0020037 heme binding | IDA PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | ACCEPT | Summary: Direct heme transfer assays confirm PGRMC1 binds and donates heme. Core MF. Reason: Direct experimental support for core heme binding activity. Supporting Evidence: PMID:27599036 In vitro heme transfer experiments showed that purified PGRMC1 was able to donate heme to apo-cytochrome b 5 . |
| GO:0001540 amyloid-beta binding | TAS PMID:26871627 The Cellular Phase of Alzheimer's Disease. | KEEP AS NON CORE | Summary: Sigma-2/PGRMC1 has been proposed as a critical neuronal receptor for Abeta-42 oligomers in Alzheimer's disease, with siRNA knockdown of PGRMC1 in cultured neurons reducing >90% of Abeta oligomer binding (Izzo et al. 2014 PMID:25390692; this annotation cites the De Strooper & Karran 2016 Cell review). Subsequent work clarifies that TMEM97 (sigma-2 receptor) is the gene product corresponding to the sigma-2 binding site and that PGRMC1 contributes as a complex member, so direct PGRMC1-Abeta binding has been debated. Keep as non-core given its disease relevance but acknowledge it is complex-mediated. Reason: Disease-context interaction at the plasma-membrane sigma-2 complex; not the core (heme-binding) activity. Direct vs complex-mediated binding remains debated. Supporting Evidence: PMID:25390692 We have identified the sigma-2/PGRMC1 protein as a critical receptor mediating greater than 90% of Abeta oligomer binding to neurons and their downstream synaptotoxic effects. |
| GO:0044297 cell body | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Parent of neuronal cell body; uninformative. Reason: Redundant with GO:0043025 neuronal cell body. |
| GO:0005783 endoplasmic reticulum | TAS PMID:25390692 Alzheimer's therapeutics targeting amyloid beta 1-42 oligome... | ACCEPT | Summary: Duplicate of GO:0005783 IBA annotation. ER is the core localisation. Reason: Core localisation, multiply supported. Supporting Evidence: PMID:25390692 translocates from the endoplasmic reticulum to the plasma membrane in several cell types |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6799350 | ACCEPT | Summary: Plasma membrane pool is well documented. The Reactome source (exocytosis of specific granule membrane proteins) is more about a specific pathway than the localisation itself. Reason: Genuine plasma membrane pool of PGRMC1. Supporting Evidence: PMID:30443021 Confocal microscopy and Proximity Ligation Assay studies indicated a clear co-localization of LDLR, PGRMC1 and TMEM97. |
| GO:0035579 specific granule membrane | TAS Reactome:R-HSA-6799350 | KEEP AS NON CORE | Summary: Reactome-derived annotation linking PGRMC1 to neutrophil specific granule membrane (exocytosis pathway). PGRMC1 has been detected in neutrophil granule-membrane proteomics but this is a niche tissue context and not functionally characterised as a core role. Reason: Cell-type-specific granule-membrane localisation in neutrophils; peripheral to PGRMC1's general biology. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput membrane-proteome study of NK cells identified PGRMC1 in membrane fractions; uninformative generic membrane annotation. Reason: Generic "membrane" is uninformative; more specific ER/plasma-membrane annotations are already present. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0005496 steroid binding | TAS PMID:9705155 Cloning and tissue expression of two putative steroid membra... | KEEP AS NON CORE | Summary: Original 1998 cloning paper that named PGRMC1 (Hpr6.6) a "putative steroid membrane receptor" based on homology to a porcine progesterone-binding protein. As above, direct steroid binding by PGRMC1 alone is equivocal; the annotation is historically motivated. Retain as non-core. Reason: Historical, putative annotation. Direct steroid binding by purified PGRMC1 cytosolic domain has not been robustly demonstrated; contemporary syntheses place heme binding (not steroid binding) as the core MF. Supporting Evidence: PMID:9705155 We have cloned two human putative steroid binding membrane proteins, termed Hpr6.6 and Dg6. |
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Download this section (compressed HTML)Q: Is direct, high-affinity progesterone binding by purified, full-length membrane-embedded PGRMC1 reproducible across independent groups, or is the historical "progesterone receptor" naming purely a misnomer derived from homology and indirect cellular effects?
Q: What is the in vivo stoichiometry and dynamics of the PGRMC1-CYP complex on the ER membrane, and how does heme loading state shift CYP isoform preference?
Q: Is the PGRMC1-FECH interaction physiologically required for heme synthesis in mammalian cells in vivo, or does it primarily fine-tune product release in specific tissues (e.g., erythroid)?
Experiment: Conditionally delete Pgrmc1 in mouse hepatocytes and rescue with WT vs. Y113F (heme-binding deficient) vs. C129S vs. Y113F/C129S double mutants; measure CYP3A4 protein, drug-clearance pharmacokinetics, and acetaminophen hepatotoxicity.
Hypothesis: Heme-loaded PGRMC1 dimers, but not apo-PGRMC1 monomers, are required for microsomal CYP3A4-mediated drug clearance in hepatocytes.
Experiment: Compare LDL internalisation kinetics in PGRMC1-KO HeLa cells reconstituted with WT vs. Y113F vs. C129S PGRMC1; test whether CORM-3 (CO donor) phenocopies heme-binding loss for LDL uptake.
Hypothesis: The TMEM97/PGRMC1/LDLR complex requires PGRMC1's heme-dependent dimerisation for accelerated LDL endocytosis.
Experiment: Use isotopically labelled heme pulse-chase combined with FECH-, PGRMC1-, and double-knockout cells to follow heme flux from mitochondria to ER-resident apo-hemoproteins, with vs. without PGRMC1 add-back.
Hypothesis: PGRMC1 functions as a heme chaperone, transferring heme from the FECH-containing mitochondrial heme metabolon to apo-CYPs and apo-cytochrome b5 in the ER.
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