STAR is a START-domain cholesterol-binding and transfer protein that promotes acute steroid hormone synthesis in adrenal and gonadal steroidogenic cells. It acts at the mitochondrial outer membrane to facilitate delivery of cholesterol to the inner-membrane enzyme CYP11A1, which converts cholesterol to pregnenolone. After acting, STAR is imported into the mitochondrial matrix. Its cholesterol-delivery function supports both adrenal and gonadal hormone production; loss-of-function variants cause congenital lipoid adrenal hyperplasia. Steroidogenic tissues such as the placenta can use STAR-independent cholesterol delivery.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006694 steroid biosynthetic process | IBA GO_REF:0000033 | MODIFY | Summary: STAR-mediated cholesterol delivery participates in steroid hormone biosynthesis. Reason: Refine this broad steroid-biosynthesis annotation to the already annotated steroid hormone biosynthetic process. STAR supplies substrate through its own cholesterol-transfer activity; the evidence is functional reconstitution as well as human deficiency, not necessity alone. Adrenal and gonadal contexts are both supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000253339 SUPPORTS TRANSFER Cached PAINT identifies the supporting IBD at this node. The broad inherited biological claim remains supported; refinement specifies the biosynthetic process documented by target evidence rather than rejecting the node placement or its descendant evidence. Proposed replacements: steroid hormone biosynthetic process Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0032367 intracellular cholesterol transport | IBA GO_REF:0000033 | ACCEPT | Summary: STAR facilitates intracellular cholesterol delivery from the mitochondrial outer to inner membrane. Reason: Cholesterol transport is the directly executed process. Primary vesicle-transfer and functional reconstitution evidence complements the original source, while the localization experiments place productive STAR action at the outer membrane. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. |
| GO:0015485 cholesterol binding | IBA GO_REF:0000033 | ACCEPT | Summary: The STAR START domain binds cholesterol. Reason: PMID:18403318 actually includes an N62-STAR/StarD1 comparator in direct radiolabeled cholesterol-binding experiments; its STARD4-focused title does not make the STAR annotation a misattribution. Cholesterol binding supplies the substrate-recognition component of transfer. Supporting Evidence: PMID:18403318 At 2 ΞΌM protein, all [ 14 C]cholesterol added was bound to the protein, at a stoichiometry of 1:0.9 (StarD4/cholesterol) ( Fig. 3 ), similar to (N62) StarD1 and StarD5 ( Fig. 3 ). |
| GO:0050810 regulation of steroid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for regulation of steroid biosynthesis. This captures StAR's defining role as the ACUTE regulator of steroidogenesis: cholesterol delivery across the mitochondrial membranes is rate-limiting, and StAR abundance (a labile protein induced by tropic hormones) sets the pace of steroid output. Reason: STAR controls substrate delivery and thereby acutely changes steroidogenic flux: human STAR reconstitution increases pregnenolone production. This is a regulatory transport role, not a claim that STAR catalyzes steroid oxidation. Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | ACCEPT | Summary: STAR has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The source describes active outer-membrane constructs and a distinction between transient outer-membrane action and targeting to the matrix; curated UniProt records both locations. Both support mitochondrial localization. Retaining the root claim does not assign cholesterol-transfer activity to the matrix; the separate outer-membrane and matrix annotations remain unchanged. The InterPro source remains an electronic assignment, independently corroborated by the localization/function evidence. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/STAR/STAR-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell electronic annotation to the mitochondrial outer membrane, the functional site of action of StAR. Reason: Consistent with experimental evidence that StAR acts on the outer mitochondrial membrane (see the EXP/IDA annotations from PMID:12530629). Supporting Evidence: PMID:17433772 outer to inner mitochondrial membrane, but acts exclusively on the outer |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0006694 steroid biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: STAR-mediated cholesterol delivery participates in steroid hormone biosynthesis. Reason: Refine this broad steroid-biosynthesis annotation to the already annotated steroid hormone biosynthetic process. STAR supplies substrate through its own cholesterol-transfer activity; the evidence is functional reconstitution as well as human deficiency, not necessity alone. Adrenal and gonadal contexts are both supported. Proposed replacements: steroid hormone biosynthetic process Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0008289 lipid binding | IEA GO_REF:0000002 | MODIFY | Summary: The STAR START domain binds cholesterol. Reason: PMID:18403318 actually includes an N62-STAR/StarD1 comparator in direct radiolabeled cholesterol-binding experiments; its STARD4-focused title does not make the STAR annotation a misattribution. Cholesterol binding supplies the substrate-recognition component of transfer. Proposed replacements: cholesterol binding Supporting Evidence: PMID:18403318 At 2 ΞΌM protein, all [ 14 C]cholesterol added was bound to the protein, at a stoichiometry of 1:0.9 (StarD4/cholesterol) ( Fig. 3 ), similar to (N62) StarD1 and StarD5 ( Fig. 3 ). |
| GO:0015485 cholesterol binding | IEA GO_REF:0000002 | ACCEPT | Summary: The STAR START domain binds cholesterol. Reason: PMID:18403318 actually includes an N62-STAR/StarD1 comparator in direct radiolabeled cholesterol-binding experiments; its STARD4-focused title does not make the STAR annotation a misattribution. Cholesterol binding supplies the substrate-recognition component of transfer. Supporting Evidence: PMID:18403318 At 2 ΞΌM protein, all [ 14 C]cholesterol added was bound to the protein, at a stoichiometry of 1:0.9 (StarD4/cholesterol) ( Fig. 3 ), similar to (N62) StarD1 and StarD5 ( Fig. 3 ). |
| GO:0015918 sterol transport | IEA GO_REF:0000117 | MODIFY | Summary: ARBA electronic annotation for sterol transport. Correct at a broad level; cholesterol is a sterol, and StAR transports it between mitochondrial membranes. The more specific term intracellular cholesterol transport (GO:0032367) is separately annotated with experimental support. Reason: Refine to the existing intracellular cholesterol transport process, the physiologically characterized sterol-delivery role in steroidogenic cells. This does not claim that STAR can never interact with another sterol. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0042446 hormone biosynthetic process | IEA GO_REF:0000117 | MODIFY | Summary: ARBA electronic annotation for hormone biosynthetic process. StAR is required for steroid HORMONE synthesis, so this is correct but the more specific steroid hormone biosynthetic process (GO:0120178) is preferable. Reason: The hormones StAR contributes to are specifically steroid hormones; the more precise steroid hormone biosynthetic process term (also annotated) better captures this. Proposed replacements: steroid hormone biosynthetic process Supporting Evidence: PMID:7892608 regulatory protein, which enhances the mitochondrial conversion of cholesterol |
| GO:0120020 cholesterol transfer activity | IEA GO_REF:0000002 | ACCEPT | Summary: STAR transfers cholesterol between membranes. Reason: The original source supports STAR-dependent mitochondrial cholesterol delivery; primary vesicle reconstitution in PMID:12372832 independently demonstrates cholesterol transfer without vesicle fusion or exchange of CYP11A1. Human cellular reconstitution and loss-of-function findings establish its adrenal/gonadal relevance. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional |
| GO:0120178 steroid hormone biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation for steroid hormone biosynthetic process. StAR initiates steroid hormone synthesis by delivering cholesterol for conversion to pregnenolone. Reason: Specific and correct process term; StAR is indispensable to adrenal and gonadal steroid hormone synthesis. Supporting Evidence: PMID:7892608 that this protein is indispensable normal adrenal and gonadal steroidogenesis. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IntAct-curated binary protein-protein interaction (IPI) from a proteome-scale interactome study (interactor MAGEA11, P43364-2). The bare term protein binding is uninformative about StAR's actual function. Reason: The cited interaction study supports a physical association, but bare protein binding does not identify a functional molecular activity. Remove this uninformative annotation under the protein-binding policy without rejecting the reported interaction or inferring a more specific activity from it. Supporting Evidence: file:human/STAR/STAR-uniprot.txt P49675; P43364-2: MAGEA11 |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: IntAct-curated binary interaction (IPI) from a systematic interactome perturbation study (interactor G5E962 / MAGEA11). Uninformative protein binding term. Reason: The cited interaction study supports a physical association, but bare protein binding does not identify a functional molecular activity. Remove this uninformative annotation under the protein-binding policy without rejecting the reported interaction or inferring a more specific activity from it. Supporting Evidence: file:human/STAR/STAR-uniprot.txt P49675; G5E962: MAGEA11 |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: IntAct-curated binary interaction (IPI) from an alternative-splicing interactome study (interactor P43364 / MAGEA11). Uninformative protein binding term. Reason: The cited interaction study supports a physical association, but bare protein binding does not identify a functional molecular activity. Remove this uninformative annotation under the protein-binding policy without rejecting the reported interaction or inferring a more specific activity from it. Supporting Evidence: file:human/STAR/STAR-uniprot.txt P49675; P43364: MAGEA11 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IntAct-curated binary interactions (IPI) from the HuRI reference human interactome (interactors incl. O60906/SMPD2, P43364/MAGEA11, Q15276/RABEP1, Q6RW13-2/AGTRAP, Q6ZPD8/DGAT2L6, Q8IZR5-2/CMTM4, Q9UNK0/STX8). Bare protein binding, uninformative. Reason: The cited interaction study supports a physical association, but bare protein binding does not identify a functional molecular activity. Remove this uninformative annotation under the protein-binding policy without rejecting the reported interaction or inferring a more specific activity from it. Supporting Evidence: file:human/STAR/STAR-uniprot.txt P49675; O60906: SMPD2 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IntAct-curated binary interaction (IPI) from a neurodegenerative-disease interactome study (interactor P42858 / HTT, huntingtin). Uninformative protein binding term. Reason: The cited interaction study supports a physical association, but bare protein binding does not identify a functional molecular activity. Remove this uninformative annotation under the protein-binding policy without rejecting the reported interaction or inferring a more specific activity from it. Supporting Evidence: file:human/STAR/STAR-uniprot.txt P49675; P42858: HTT |
| GO:0006700 C21-steroid hormone biosynthetic process | TAS Reactome:R-HSA-196108 | ACCEPT | Summary: Reactome traceable annotation placing StAR in C21-steroid (pregnane) hormone biosynthesis, via the Pregnenolone biosynthesis pathway. Correct: StAR delivers cholesterol so CYP11A1 can generate pregnenolone (a C21-steroid), the precursor of glucocorticoids, mineralocorticoids and progestins. Reason: Accurate pathway placement; pregnenolone and downstream C21 steroids are the immediate products of the StAR-enabled step. Supporting Evidence: PMID:7761400 in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: STAR participates in the cholesterol utilization pathway by delivering its substrate. Reason: The existing pathway annotation concerns cholesterol handling in the steroidogenic pathway, with direct transfer activity established independently. It does not assert that STAR enzymatically oxidizes or cleaves cholesterol. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. |
| GO:0005759 mitochondrial matrix | EXP PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: Direct experimental localization of StAR to the mitochondrial outer membrane, its functional site of action. Reason: The outer mitochondrial membrane is where StAR acts; constructs immobilizing StAR at the OMM were the only active ones. Supporting Evidence: PMID:12530629 matrix side of the IMM. Only the constructs at the OMM were active |
| GO:0006704 glucocorticoid biosynthetic process | IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: STAR provides mitochondrial cholesterol delivery for adrenal glucocorticoid biosynthesis. Reason: This is direct pathway participation by a cholesterol-transfer protein supplying the biosynthetic substrate, not a claim that STAR chemically makes glucocorticoids. Human functional reconstitution and adrenal deficiency support the role; the cached adrenal GO-CAM likewise nests STAR cholesterol transport in glucocorticoid biosynthesis. Gonadal roles are retained separately. Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0032367 intracellular cholesterol transport | IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: STAR facilitates intracellular cholesterol delivery from the mitochondrial outer to inner membrane. Reason: Cholesterol transport is the directly executed process. Primary vesicle-transfer and functional reconstitution evidence complements the original source, while the localization experiments place productive STAR action at the outer membrane. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. |
| GO:0032367 intracellular cholesterol transport | EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an... | ACCEPT | Summary: STAR facilitates intracellular cholesterol delivery from the mitochondrial outer to inner membrane. Reason: Cholesterol transport is the directly executed process. Primary vesicle-transfer and functional reconstitution evidence complements the original source, while the localization experiments place productive STAR action at the outer membrane. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. |
| GO:0120020 cholesterol transfer activity | EXP PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: STAR transfers cholesterol between membranes. Reason: The original source supports STAR-dependent mitochondrial cholesterol delivery; primary vesicle reconstitution in PMID:12372832 independently demonstrates cholesterol transfer without vesicle fusion or exchange of CYP11A1. Human cellular reconstitution and loss-of-function findings establish its adrenal/gonadal relevance. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional |
| GO:0120020 cholesterol transfer activity | IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: STAR transfers cholesterol between membranes. Reason: The original source supports STAR-dependent mitochondrial cholesterol delivery; primary vesicle reconstitution in PMID:12372832 independently demonstrates cholesterol transfer without vesicle fusion or exchange of CYP11A1. Human cellular reconstitution and loss-of-function findings establish its adrenal/gonadal relevance. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional |
| GO:0120020 cholesterol transfer activity | EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an... | ACCEPT | Summary: STAR transfers cholesterol between membranes. Reason: The original source supports STAR-dependent mitochondrial cholesterol delivery; primary vesicle reconstitution in PMID:12372832 independently demonstrates cholesterol transfer without vesicle fusion or exchange of CYP11A1. Human cellular reconstitution and loss-of-function findings establish its adrenal/gonadal relevance. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional |
| GO:0005741 mitochondrial outer membrane | EXP PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only... | ACCEPT | Summary: Experimental is_active_in annotation: StAR exerts its cholesterol-transfer activity at the mitochondrial outer membrane. This is the most precise statement of where StAR functions. Reason: Directly demonstrated: only OMM-immobilized StAR constructs were active, establishing the outer membrane as its site of action. Supporting Evidence: PMID:12530629 matrix side of the IMM. Only the constructs at the OMM were active |
| GO:0005741 mitochondrial outer membrane | EXP PMID:17433772 Steroidogenic acute regulatory protein (StAR), a novel mitoc... | ACCEPT | Summary: Experimental is_active_in annotation confirming StAR acts exclusively on the mitochondrial outer membrane. Reason: Consistent with the biophysical and cell-biology evidence that StAR acts only at the outer membrane; core functional localization. Supporting Evidence: PMID:17433772 outer to inner mitochondrial membrane, but acts exclusively on the outer |
| GO:0032367 intracellular cholesterol transport | EXP PMID:17433772 Steroidogenic acute regulatory protein (StAR), a novel mitoc... | ACCEPT | Summary: STAR facilitates intracellular cholesterol delivery from the mitochondrial outer to inner membrane. Reason: Cholesterol transport is the directly executed process. Primary vesicle-transfer and functional reconstitution evidence complements the original source, while the localization experiments place productive STAR action at the outer membrane. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. |
| GO:0120020 cholesterol transfer activity | EXP PMID:17433772 Steroidogenic acute regulatory protein (StAR), a novel mitoc... | ACCEPT | Summary: STAR transfers cholesterol between membranes. Reason: The original source supports STAR-dependent mitochondrial cholesterol delivery; primary vesicle reconstitution in PMID:12372832 independently demonstrates cholesterol transfer without vesicle fusion or exchange of CYP11A1. Human cellular reconstitution and loss-of-function findings establish its adrenal/gonadal relevance. Supporting Evidence: PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional |
| GO:0006704 glucocorticoid biosynthetic process | EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an... | ACCEPT | Summary: STAR provides mitochondrial cholesterol delivery for adrenal glucocorticoid biosynthesis. Reason: This is direct pathway participation by a cholesterol-transfer protein supplying the biosynthetic substrate, not a claim that STAR chemically makes glucocorticoids. Human functional reconstitution and adrenal deficiency support the role; the cached adrenal GO-CAM likewise nests STAR cholesterol transport in glucocorticoid biosynthesis. Gonadal roles are retained separately. Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
| GO:0140104 molecular carrier activity | TAS Reactome:R-HSA-196126 | MODIFY | Summary: Reactome traceable annotation to the broad molecular carrier activity term. StAR is indeed a cholesterol carrier, but the specific term cholesterol transfer activity (GO:0120020) is far more informative and is well supported experimentally. Reason: The generic molecular carrier activity should be replaced by the specific cholesterol transfer activity, which precisely describes StAR's molecular function. Proposed replacements: cholesterol transfer activity Supporting Evidence: PMID:17433772 StAR can transfer cholesterol between synthetic liposomes in |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: STAR has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The source describes active outer-membrane constructs and a distinction between transient outer-membrane action and targeting to the matrix; curated UniProt records both locations. Both support mitochondrial localization. Retaining the root claim does not assign cholesterol-transfer activity to the matrix; the separate outer-membrane and matrix annotations remain unchanged. The original HTP compendium source is retained without claiming a new target-specific identification or topology measurement. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/STAR/STAR-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9839105 | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9839149 | KEEP AS NON CORE | Summary: STAR is imported into the mitochondrial matrix after its productive outer-membrane action. Reason: The matrix is a genuine post-import location but not the established site of STAR cholesterol-transfer activity. Reactome degradation/binding events concern this imported pool; retain its localization without assigning STAR a protease function. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mitochondrion matrix PMID:12530629 rather than in the location (the matrix) to which it is targeted. |
| GO:0015485 cholesterol binding | IDA PMID:18403318 Intracellular cholesterol transporter StarD4 binds free chol... | ACCEPT | Summary: The STAR START domain binds cholesterol. Reason: PMID:18403318 actually includes an N62-STAR/StarD1 comparator in direct radiolabeled cholesterol-binding experiments; its STARD4-focused title does not make the STAR annotation a misattribution. Cholesterol binding supplies the substrate-recognition component of transfer. Supporting Evidence: PMID:18403318 At 2 ΞΌM protein, all [ 14 C]cholesterol added was bound to the protein, at a stoichiometry of 1:0.9 (StarD4/cholesterol) ( Fig. 3 ), similar to (N62) StarD1 and StarD5 ( Fig. 3 ). |
| GO:0070859 positive regulation of bile acid biosynthetic process | IDA PMID:18403318 Intracellular cholesterol transporter StarD4 binds free chol... | KEEP AS NON CORE | Summary: STAR overexpression enhances bile-acid synthesis in a cultured-hepatocyte assay. Reason: Full-text inspection overturns the previous wrong-paralog suspicion: PMID:18403318 includes StarD1 as an experimental comparator and reports an approximately tenfold increase in bile-acid synthesis after its overexpression in primary mouse hepatocytes. Retain this supported context-dependent activity as non-core; it does not establish normal adrenal STAR as a bile-acid enzyme or imply tissue expression from its family. Supporting Evidence: PMID:18403318 rates similar to that observed after StarD1 overexpression (10-fold increase). |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-196126 | UNDECIDED | Summary: The Reactome assignment to intermembrane space is not resolved by the outer-membrane activity experiments. Reason: Reactome places the transport-associated STAR entity in this compartment, but cholesterol crossing the intermembrane space does not establish that STAR operates there. PMID:12530629 tests compartment-restricted constructs and finds activity only at the outer membrane. This does not exclude transient passage during mitochondrial import; retain uncertainty about the distinct physical localization rather than assume it from cargo movement. Supporting Evidence: PMID:12530629 Only the constructs at the OMM were active, either in vivo or in vitro. Reactome:R-HSA-196126 where STAR steroidogenic acute regulatory protein mediates its delivery to the mitochondrial inner membrane |
| GO:0006694 steroid biosynthetic process | TAS PMID:7761400 Human steroidogenic acute regulatory protein: functional act... | MODIFY | Summary: STAR-mediated cholesterol delivery participates in steroid hormone biosynthesis. Reason: Refine this broad steroid-biosynthesis annotation to the already annotated steroid hormone biosynthetic process. STAR supplies substrate through its own cholesterol-transfer activity; the evidence is functional reconstitution as well as human deficiency, not necessity alone. Adrenal and gonadal contexts are both supported. Proposed replacements: steroid hormone biosynthetic process Supporting Evidence: PMID:7761400 Human StAR, coexpressed in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone synthesis > 4-fold. PMID:7892608 In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional PMID:12372832 Thus StAR can transfer cholesterol between synthetic membranes without other protein components found in mitochondria. |
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Download this section (compressed HTML)Q: Which cholesterol-binding partners at the outer mitochondrial membrane (e.g. TSPO, VDAC1) form the functional StAR transfer complex in vivo, and are any of the high-throughput interactome hits functionally relevant?
Q: How is StAR's transient outer-membrane residence and rapid matrix import/ degradation coupled to the minute-scale acute regulation of steroid output?
Experiment: Reconstitute StAR-mediated cholesterol transfer with defined outer-membrane proteins to define the minimal functional transfer machinery.
Experiment: Systematically test whether any curated StAR protein-protein interactions (IntAct) modulate cholesterol transfer or steroidogenic output.
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