STAR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006694 steroid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation placing STAR in the steroid biosynthetic process. Correct at a broad level: StAR is essential for steroidogenesis by delivering cholesterol to CYP11A1 for conversion to pregnenolone, the committed precursor of all steroid hormones. StAR itself is not a biosynthetic enzyme but is indispensable to the pathway. Reason: Well supported across evidence types. StAR increases pregnenolone synthesis in reconstituted steroidogenic cells and its loss abolishes all adrenal and gonadal steroid synthesis. Supporting Evidence: PMID:7761400 in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone PMID:7892608 regulatory protein, which enhances the mitochondrial conversion of cholesterol
GO:0032367 intracellular cholesterol transport	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation for intracellular cholesterol transport. This is a core biological-process role for StAR, which moves cholesterol from the outer to the inner mitochondrial membrane. Reason: Directly supported by experimental data: StAR moves large amounts of cholesterol between the mitochondrial membranes. Represents a core function of the gene. Supporting Evidence: PMID:17433772 biology experiments show that StAR moves large amounts of cholesterol from the
GO:0015485 cholesterol binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation for cholesterol binding, a core molecular function of the START domain of StAR. StAR sequesters a single cholesterol molecule in its hydrophobic START pocket. Reason: Cholesterol binding is the fundamental biochemical property of the StAR START domain and is directly demonstrated experimentally (see the IDA annotation from PMID:18403318). This IBA is consistent and core. Supporting Evidence: PMID:18403318 of the cholesterol binding START domain proteins StarD1 and StarD5.
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-mediated cholesterol traversal is the rate-limiting, acutely regulated step of steroid hormone synthesis; regulation of steroid biosynthesis is a core aspect of its biology, distinct from being a pathway enzyme. Supporting Evidence: PMID:7761400 in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone
GO:0005739 mitochondrion	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation to the mitochondrion. Correct but unspecific; StAR is a mitochondrially targeted protein. Reason: True but general. StAR carries an N-terminal mitochondrial transit peptide and localizes to mitochondria; a more specific term (mitochondrial outer membrane) is separately annotated with experimental support. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Mediates the transfer
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: UniProt SubCell electronic annotation to the mitochondrial matrix. StAR is imported into the matrix, but experimental work shows it exerts its activity only transiently at the outer membrane, not in the matrix. Reason: The mature protein does reach the matrix (where it is imported and degraded), so the location is real, but the matrix is explicitly NOT where StAR is functional; its site of action is the outer mitochondrial membrane. Retain as a non-core localization. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
GO:0006694 steroid biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation duplicating the IBA/TAS steroid biosynthetic process assignment. Correct. Reason: Same well-supported process role as the IBA and TAS annotations to this term; the electronic mapping is appropriate for a StAR-family protein. Supporting Evidence: PMID:7892608 regulatory protein, which enhances the mitochondrial conversion of cholesterol
GO:0008289 lipid binding	IEA GO_REF:0000002	MODIFY	Summary: InterPro (START/StAR-like domain) electronic annotation for the broad term lipid binding. Correct but less informative than the specific cholesterol binding term. Reason: StAR's ligand is specifically cholesterol; the more specific molecular function cholesterol binding (GO:0015485), also annotated, should be preferred over the general parent lipid binding. Proposed replacements: cholesterol binding Supporting Evidence: PMID:18403318 of the cholesterol binding START domain proteins StarD1 and StarD5.
GO:0015485 cholesterol binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation for cholesterol binding, the core molecular function of StAR. Duplicates the IBA and IDA annotations to this term. Reason: Core molecular function, well supported by experimental cholesterol binding data and by the START-domain family assignment. Supporting Evidence: PMID:18403318 of the cholesterol binding START domain proteins StarD1 and StarD5.
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: Accurate but general; StAR's cargo is specifically cholesterol, so the more precise intracellular cholesterol transport / cholesterol transport terms better describe the function. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:17433772 biology experiments show that StAR moves large amounts of cholesterol from the
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: InterPro-based electronic annotation for cholesterol transfer activity, the core molecular function of StAR. Duplicates the EXP/IDA annotations to this term. Reason: Core molecular function: StAR transfers cholesterol between membranes. Strongly supported by experimental data and by the StAR-family InterPro signature. Supporting Evidence: PMID:17433772 StAR can transfer cholesterol between synthetic liposomes in
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.	MARK AS OVER ANNOTATED	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: Per curation guidance, bare protein binding conveys no functional information. This is a high-throughput interactome hit with no established role in StAR's cholesterol-transfer / steroidogenic function; retained but flagged as over-annotated rather than removed.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: IntAct-curated binary interaction (IPI) from a systematic interactome perturbation study (interactor G5E962 / MAGEA11). Uninformative protein binding term. Reason: High-throughput interactome interaction with no demonstrated relevance to StAR's molecular function; bare protein binding is not informative. Retained but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: IntAct-curated binary interaction (IPI) from an alternative-splicing interactome study (interactor P43364 / MAGEA11). Uninformative protein binding term. Reason: High-throughput interactome hit; no established functional role in steroidogenesis. Bare protein binding is uninformative; retained but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	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: Systematic Y2H reference-map interactions; none is an established functional partner in StAR's cholesterol-transfer role. Bare protein binding conveys no functional information; retained but flagged.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IntAct-curated binary interaction (IPI) from a neurodegenerative-disease interactome study (interactor P42858 / HTT, huntingtin). Uninformative protein binding term. Reason: High-throughput interactome hit unrelated to StAR's characterized function; bare protein binding is not informative. Retained but flagged as over-annotated.
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: UniPathway-based electronic annotation to cholesterol metabolic process. Correct but broad; StAR's contribution is specifically the intracellular transport of cholesterol feeding into steroid synthesis. Reason: StAR participates in cholesterol metabolism/handling; UniProt lists its pathway as cholesterol metabolism. Broad but not wrong. Supporting Evidence: file:human/STAR/STAR-uniprot.txt Steroid metabolism; cholesterol metabolism.
GO:0005759 mitochondrial matrix	EXP PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only...	KEEP AS NON CORE	Summary: Experimental localization of StAR to the mitochondrial matrix. StAR is targeted to and imported into the matrix, but the same study shows it is functional only at the outer membrane, occupying the matrix location only after acting. Reason: Real localization (the protein is imported into the matrix), but per this study the matrix is explicitly NOT the site of StAR activity; its function is exerted at the outer membrane. Retain as non-core localization. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
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: Experimental annotation placing StAR in glucocorticoid biosynthesis, a downstream C21-steroid output that depends on StAR-mediated cholesterol delivery in the adrenal cortex. Reason: StAR is required for adrenal steroidogenesis, including glucocorticoid synthesis; loss of StAR causes glucocorticoid deficiency (lipoid CAH). Supporting Evidence: PMID:7892608 that this protein is indispensable normal adrenal and gonadal steroidogenesis.
GO:0032367 intracellular cholesterol transport	IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only...	ACCEPT	Summary: Direct experimental annotation for intracellular cholesterol transport, a core StAR function: moving cholesterol from the outer to the inner mitochondrial membrane. Reason: Core biological process directly demonstrated; StAR moves large amounts of cholesterol between the mitochondrial membranes. Supporting Evidence: PMID:17433772 biology experiments show that StAR moves large amounts of cholesterol from the
GO:0032367 intracellular cholesterol transport	EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an...	ACCEPT	Summary: Experimental annotation for intracellular cholesterol transport based on loss-of-function evidence: StAR mutations abolish the mitochondrial cholesterol-to-pregnenolone conversion. Reason: Human loss-of-function (lipoid CAH) genetically establishes StAR's indispensable role in delivering cholesterol for steroidogenesis. Core function. Supporting Evidence: PMID:7892608 regulatory protein, which enhances the mitochondrial conversion of cholesterol
GO:0120020 cholesterol transfer activity	EXP PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only...	ACCEPT	Summary: Experimental annotation for cholesterol transfer activity, the core molecular function of StAR at the outer mitochondrial membrane. Reason: StAR transfers cholesterol between membranes; this is its defining biochemical activity (a lipid transfer, not an enzymatic transformation). Supporting Evidence: PMID:17433772 StAR can transfer cholesterol between synthetic liposomes in
GO:0120020 cholesterol transfer activity	IDA PMID:12530629 The steroidogenic acute regulatory protein, StAR, works only...	ACCEPT	Summary: Direct experimental annotation (IDA) for cholesterol transfer activity; duplicates the EXP annotation from the same study. Reason: Core molecular function, directly demonstrated. StAR moves cholesterol from the outer to the inner mitochondrial membrane. Supporting Evidence: PMID:17433772 outer to inner mitochondrial membrane, but acts exclusively on the outer
GO:0120020 cholesterol transfer activity	EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an...	ACCEPT	Summary: Experimental annotation for cholesterol transfer activity supported by loss-of-function evidence: non-functional StAR mutants cannot promote the cholesterol-to-pregnenolone conversion. Reason: Core molecular function; StAR mutations that abolish steroidogenesis establish the transfer activity as essential. Supporting Evidence: PMID:7892608 regulatory protein, which enhances the mitochondrial conversion of cholesterol
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: Experimental annotation for intracellular cholesterol transport; StAR moves large amounts of cholesterol from the outer to the inner mitochondrial membrane. Reason: Core biological process, directly supported by cell-biology experiments. Supporting Evidence: PMID:17433772 biology experiments show that StAR moves large amounts of cholesterol from the
GO:0120020 cholesterol transfer activity	EXP PMID:17433772 Steroidogenic acute regulatory protein (StAR), a novel mitoc...	ACCEPT	Summary: Experimental annotation for cholesterol transfer activity; StAR transfers cholesterol between membranes (demonstrated in vitro between liposomes and in cells between the mitochondrial membranes). Reason: Core molecular function, well supported. This transfer activity, not any enzymatic reaction, is StAR's defining biochemical role. Supporting Evidence: PMID:17433772 StAR can transfer cholesterol between synthetic liposomes in
GO:0006704 glucocorticoid biosynthetic process	EXP PMID:7892608 Role of steroidogenic acute regulatory protein in adrenal an...	ACCEPT	Summary: Experimental annotation for glucocorticoid biosynthesis based on human loss-of-function: StAR mutations impair synthesis of all adrenal steroids, including glucocorticoids. Reason: StAR is indispensable for adrenal steroidogenesis; its loss causes glucocorticoid (and mineralocorticoid) deficiency in lipoid CAH. Supporting Evidence: PMID:7892608 that this protein is indispensable normal adrenal and gonadal steroidogenesis.
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: High-throughput proteomics localization of StAR to the mitochondrion, consistent with its established mitochondrial localization. Reason: StAR is a bona fide mitochondrial protein; the high-confidence mitochondrial proteome supports this general localization (a more specific outer-membrane term is separately annotated experimentally). Supporting Evidence: PMID:34800366 high-confidence human mitochondrial proteome
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838081	KEEP AS NON CORE	Summary: Reactome traceable annotation placing StAR in the mitochondrial matrix, in the context of LONP1-mediated degradation of matrix proteins. This reflects that matrix-imported StAR is a substrate for matrix proteases, not that the matrix is its functional site. Reason: Localization to the matrix is real (StAR is imported and turned over there) but non-core; its site of action is the outer membrane. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838093	KEEP AS NON CORE	Summary: Reactome traceable annotation to the mitochondrial matrix in the context of LONP1 binding matrix proteins. Same rationale: matrix-imported StAR is a protease substrate; the matrix is not its functional site. Reason: Real but non-core localization; StAR functions at the outer membrane, not in the matrix. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9839105	KEEP AS NON CORE	Summary: Reactome traceable annotation to the mitochondrial matrix in the context of AFG3L2 degrading matrix proteins. Reflects matrix protein turnover, not the site of StAR activity. Reason: Real but non-core localization; StAR's functional site is the outer membrane. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9839149	KEEP AS NON CORE	Summary: Reactome traceable annotation to the mitochondrial matrix in the context of AFG3L2 binding matrix proteins. Same rationale as the other matrix degradation modules. Reason: Real but non-core localization; StAR is functional at the outer membrane, not the matrix. Supporting Evidence: PMID:12530629 only on the OMM, providing an unusual example of a protein that exerts its
GO:0015485 cholesterol binding	IDA PMID:18403318 Intracellular cholesterol transporter StarD4 binds free chol...	ACCEPT	Summary: IDA annotation for cholesterol binding. The cited paper primarily characterizes the paralog StarD4, but explicitly states that StarD1 (STAR) is an established cholesterol-binding START domain protein used as the comparison standard, and cholesterol binding is directly demonstrated for StAR by many sources. Reason: Cholesterol binding is a well-established core molecular function of StAR; the supporting text directly names StarD1 as a cholesterol-binding START protein. Retained as core. Supporting Evidence: PMID:18403318 of the cholesterol binding START domain proteins StarD1 and StarD5.
GO:0070859 positive regulation of bile acid biosynthetic process	IDA PMID:18403318 Intracellular cholesterol transporter StarD4 binds free chol...	MARK AS OVER ANNOTATED	Summary: IDA annotation for positive regulation of bile acid biosynthesis. However, the cited study demonstrates this phenotype for the paralog StarD4 (StarD4 overexpression in hepatocytes increased bile acid synthesis), not for STAR/StARD1. STAR is not an established regulator of hepatic bile acid biosynthesis and is expressed in steroidogenic tissues, not liver. Reason: The bile-acid biosynthesis phenotype in this paper is a StarD4 property; the abstract attributes the increased bile acid synthesis to StarD4 overexpression in hepatocytes, not to STAR. Following the policy against REMOVE of experimental annotations whose full text is not verifiable, this is flagged as over-annotated rather than removed; it is not a core StAR function. Supporting Evidence: PMID:18403318 the rates of bile acid synthesis.
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-HSA-196126	KEEP AS NON CORE	Summary: Reactome traceable annotation to the mitochondrial intermembrane space, in the model of StAR delivering cholesterol from the outer toward the inner membrane. StAR necessarily traverses/works across the intermembrane space during cholesterol delivery. Reason: Consistent with StAR moving cholesterol across the intermembrane space toward the inner membrane; retained as a supporting (non-core) localization, with the outer membrane as the primary functional site. Supporting Evidence: PMID:17433772 outer to inner mitochondrial membrane, but acts exclusively on the outer
GO:0006694 steroid biosynthetic process	TAS PMID:7761400 Human steroidogenic acute regulatory protein: functional act...	ACCEPT	Summary: Traceable author statement placing StAR in steroid biosynthesis. Supported by the original functional demonstration that StAR increases pregnenolone synthesis in reconstituted steroidogenic cells. Reason: Core process role; StAR is required for the initiation of steroid biosynthesis by delivering cholesterol to CYP11A1. Supporting Evidence: PMID:7761400 in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone

📄 View Raw YAML

id: P49675
gene_symbol: STAR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  STAR (steroidogenic acute regulatory protein, StAR; also StARD1) is a
  START-domain (StAR-related lipid transfer) cholesterol-binding protein that
  mediates the rate-limiting, acute step of steroid hormone biosynthesis. It is
  not an enzyme; its molecular function is cholesterol binding and cholesterol
  transfer. StAR delivers cholesterol from the outer to the inner mitochondrial
  membrane, where the cytochrome P450 side-chain cleavage enzyme CYP11A1
  converts it to pregnenolone, the common precursor of all steroid hormones.
  Although the mature protein is imported into the mitochondrial matrix, its
  functional site of action is the mitochondrial outer membrane, which it
  occupies only transiently. STAR is expressed in steroidogenic tissues,
  principally the adrenal cortex and gonads (and kidney). Because cholesterol
  delivery across the mitochondrial membranes is rate-limiting for
  steroidogenesis, StAR is the acute (minutes-scale) regulator of steroid
  output. Loss-of-function mutations cause congenital lipoid adrenal hyperplasia
  (lipoid CAH; adrenal hyperplasia 1), a severe deficiency of all adrenal and
  gonadal steroids accompanied by lipid accumulation in steroidogenic cells.
existing_annotations:
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing STAR in the steroid biosynthetic
      process. Correct at a broad level: StAR is essential for steroidogenesis
      by delivering cholesterol to CYP11A1 for conversion to pregnenolone, the
      committed precursor of all steroid hormones. StAR itself is not a
      biosynthetic enzyme but is indispensable to the pathway.
    action: ACCEPT
    reason: >-
      Well supported across evidence types. StAR increases pregnenolone
      synthesis in reconstituted steroidogenic cells and its loss abolishes all
      adrenal and gonadal steroid synthesis.
    supported_by:
    - reference_id: PMID:7761400
      supporting_text: >-
        in COS-1 cells with cytochrome P450scc and adrenodoxin, increased
        pregnenolone
    - reference_id: PMID:7892608
      supporting_text: >-
        regulatory protein, which enhances the mitochondrial conversion of
        cholesterol
- term:
    id: GO:0032367
    label: intracellular cholesterol transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation for intracellular cholesterol transport. This is a
      core biological-process role for StAR, which moves cholesterol from the
      outer to the inner mitochondrial membrane.
    action: ACCEPT
    reason: >-
      Directly supported by experimental data: StAR moves large amounts of
      cholesterol between the mitochondrial membranes. Represents a core
      function of the gene.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: biology experiments show that StAR moves large amounts of cholesterol from the
- term:
    id: GO:0015485
    label: cholesterol binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation for cholesterol binding, a core molecular function
      of the START domain of StAR. StAR sequesters a single cholesterol molecule
      in its hydrophobic START pocket.
    action: ACCEPT
    reason: >-
      Cholesterol binding is the fundamental biochemical property of the StAR
      START domain and is directly demonstrated experimentally (see the IDA
      annotation from PMID:18403318). This IBA is consistent and core.
    supported_by:
    - reference_id: PMID:18403318
      supporting_text: of the cholesterol binding START domain proteins StarD1 and StarD5.
- term:
    id: GO:0050810
    label: regulation of steroid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      StAR-mediated cholesterol traversal is the rate-limiting, acutely
      regulated step of steroid hormone synthesis; regulation of steroid
      biosynthesis is a core aspect of its biology, distinct from being a
      pathway enzyme.
    supported_by:
    - reference_id: PMID:7761400
      supporting_text: in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro-based electronic annotation to the mitochondrion. Correct but
      unspecific; StAR is a mitochondrially targeted protein.
    action: ACCEPT
    reason: >-
      True but general. StAR carries an N-terminal mitochondrial transit peptide
      and localizes to mitochondria; a more specific term (mitochondrial outer
      membrane) is separately annotated with experimental support.
    supported_by:
    - reference_id: file:human/STAR/STAR-uniprot.txt
      supporting_text: Mediates the transfer
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell electronic annotation to the mitochondrial outer membrane,
      the functional site of action of StAR.
    action: ACCEPT
    reason: >-
      Consistent with experimental evidence that StAR acts on the outer
      mitochondrial membrane (see the EXP/IDA annotations from PMID:12530629).
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: outer to inner mitochondrial membrane, but acts exclusively on the outer
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell electronic annotation to the mitochondrial matrix. StAR is
      imported into the matrix, but experimental work shows it exerts its
      activity only transiently at the outer membrane, not in the matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      The mature protein does reach the matrix (where it is imported and
      degraded), so the location is real, but the matrix is explicitly NOT where
      StAR is functional; its site of action is the outer mitochondrial
      membrane. Retain as a non-core localization.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based electronic annotation duplicating the IBA/TAS steroid
      biosynthetic process assignment. Correct.
    action: ACCEPT
    reason: >-
      Same well-supported process role as the IBA and TAS annotations to this
      term; the electronic mapping is appropriate for a StAR-family protein.
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: regulatory protein, which enhances the mitochondrial conversion of cholesterol
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro (START/StAR-like domain) electronic annotation for the broad term
      lipid binding. Correct but less informative than the specific cholesterol
      binding term.
    action: MODIFY
    reason: >-
      StAR's ligand is specifically cholesterol; the more specific molecular
      function cholesterol binding (GO:0015485), also annotated, should be
      preferred over the general parent lipid binding.
    proposed_replacement_terms:
    - id: GO:0015485
      label: cholesterol binding
    supported_by:
    - reference_id: PMID:18403318
      supporting_text: of the cholesterol binding START domain proteins StarD1 and StarD5.
- term:
    id: GO:0015485
    label: cholesterol binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation for cholesterol binding, the core
      molecular function of StAR. Duplicates the IBA and IDA annotations to this
      term.
    action: ACCEPT
    reason: >-
      Core molecular function, well supported by experimental cholesterol
      binding data and by the START-domain family assignment.
    supported_by:
    - reference_id: PMID:18403318
      supporting_text: of the cholesterol binding START domain proteins StarD1 and StarD5.
- term:
    id: GO:0015918
    label: sterol transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    reason: >-
      Accurate but general; StAR's cargo is specifically cholesterol, so the
      more precise intracellular cholesterol transport / cholesterol transport
      terms better describe the function.
    proposed_replacement_terms:
    - id: GO:0032367
      label: intracellular cholesterol transport
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: biology experiments show that StAR moves large amounts of cholesterol from the
- term:
    id: GO:0042446
    label: hormone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    reason: >-
      The hormones StAR contributes to are specifically steroid hormones; the
      more precise steroid hormone biosynthetic process term (also annotated)
      better captures this.
    proposed_replacement_terms:
    - id: GO:0120178
      label: steroid hormone biosynthetic process
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: regulatory protein, which enhances the mitochondrial conversion of cholesterol
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation for cholesterol transfer activity,
      the core molecular function of StAR. Duplicates the EXP/IDA annotations to
      this term.
    action: ACCEPT
    reason: >-
      Core molecular function: StAR transfers cholesterol between membranes.
      Strongly supported by experimental data and by the StAR-family InterPro
      signature.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: StAR can transfer cholesterol between synthetic liposomes in
- term:
    id: GO:0120178
    label: steroid hormone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation for steroid hormone biosynthetic process. StAR
      initiates steroid hormone synthesis by delivering cholesterol for
      conversion to pregnenolone.
    action: ACCEPT
    reason: >-
      Specific and correct process term; StAR is indispensable to adrenal and
      gonadal steroid hormone synthesis.
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: that this protein is indispensable normal adrenal and gonadal steroidogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidance, bare protein binding conveys no functional
      information. This is a high-throughput interactome hit with no established
      role in StAR's cholesterol-transfer / steroidogenic function; retained but
      flagged as over-annotated rather than removed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction (IPI) from a systematic interactome
      perturbation study (interactor G5E962 / MAGEA11). Uninformative protein
      binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome interaction with no demonstrated relevance to
      StAR's molecular function; bare protein binding is not informative.
      Retained but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction (IPI) from an alternative-splicing
      interactome study (interactor P43364 / MAGEA11). Uninformative protein
      binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome hit; no established functional role in
      steroidogenesis. Bare protein binding is uninformative; retained but
      flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Systematic Y2H reference-map interactions; none is an established
      functional partner in StAR's cholesterol-transfer role. Bare protein
      binding conveys no functional information; retained but flagged.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction (IPI) from a neurodegenerative-disease
      interactome study (interactor P42858 / HTT, huntingtin). Uninformative
      protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome hit unrelated to StAR's characterized
      function; bare protein binding is not informative. Retained but flagged as
      over-annotated.
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196108
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Accurate pathway placement; pregnenolone and downstream C21 steroids are
      the immediate products of the StAR-enabled step.
    supported_by:
    - reference_id: PMID:7761400
      supporting_text: in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation to cholesterol metabolic process.
      Correct but broad; StAR's contribution is specifically the intracellular
      transport of cholesterol feeding into steroid synthesis.
    action: ACCEPT
    reason: >-
      StAR participates in cholesterol metabolism/handling; UniProt lists its
      pathway as cholesterol metabolism. Broad but not wrong.
    supported_by:
    - reference_id: file:human/STAR/STAR-uniprot.txt
      supporting_text: Steroid metabolism; cholesterol metabolism.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: EXP
  original_reference_id: PMID:12530629
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of StAR to the mitochondrial matrix. StAR is
      targeted to and imported into the matrix, but the same study shows it is
      functional only at the outer membrane, occupying the matrix location only
      after acting.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real localization (the protein is imported into the matrix), but per this
      study the matrix is explicitly NOT the site of StAR activity; its function
      is exerted at the outer membrane. Retain as non-core localization.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:12530629
  qualifier: located_in
  review:
    summary: >-
      Direct experimental localization of StAR to the mitochondrial outer
      membrane, its functional site of action.
    action: ACCEPT
    reason: >-
      The outer mitochondrial membrane is where StAR acts; constructs
      immobilizing StAR at the OMM were the only active ones.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: matrix side of the IMM. Only the constructs at the OMM were active
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12530629
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation placing StAR in glucocorticoid biosynthesis, a
      downstream C21-steroid output that depends on StAR-mediated cholesterol
      delivery in the adrenal cortex.
    action: ACCEPT
    reason: >-
      StAR is required for adrenal steroidogenesis, including glucocorticoid
      synthesis; loss of StAR causes glucocorticoid deficiency (lipoid CAH).
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: that this protein is indispensable normal adrenal and gonadal steroidogenesis.
- term:
    id: GO:0032367
    label: intracellular cholesterol transport
  evidence_type: IDA
  original_reference_id: PMID:12530629
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation for intracellular cholesterol transport, a
      core StAR function: moving cholesterol from the outer to the inner
      mitochondrial membrane.
    action: ACCEPT
    reason: >-
      Core biological process directly demonstrated; StAR moves large amounts of
      cholesterol between the mitochondrial membranes.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: biology experiments show that StAR moves large amounts of cholesterol from the
- term:
    id: GO:0032367
    label: intracellular cholesterol transport
  evidence_type: EXP
  original_reference_id: PMID:7892608
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation for intracellular cholesterol transport based on
      loss-of-function evidence: StAR mutations abolish the mitochondrial
      cholesterol-to-pregnenolone conversion.
    action: ACCEPT
    reason: >-
      Human loss-of-function (lipoid CAH) genetically establishes StAR's
      indispensable role in delivering cholesterol for steroidogenesis. Core
      function.
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: regulatory protein, which enhances the mitochondrial conversion of cholesterol
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: EXP
  original_reference_id: PMID:12530629
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for cholesterol transfer activity, the core
      molecular function of StAR at the outer mitochondrial membrane.
    action: ACCEPT
    reason: >-
      StAR transfers cholesterol between membranes; this is its defining
      biochemical activity (a lipid transfer, not an enzymatic transformation).
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: StAR can transfer cholesterol between synthetic liposomes in
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: IDA
  original_reference_id: PMID:12530629
  qualifier: enables
  review:
    summary: >-
      Direct experimental annotation (IDA) for cholesterol transfer activity;
      duplicates the EXP annotation from the same study.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated. StAR moves cholesterol
      from the outer to the inner mitochondrial membrane.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: outer to inner mitochondrial membrane, but acts exclusively on the outer
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: EXP
  original_reference_id: PMID:7892608
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for cholesterol transfer activity supported by
      loss-of-function evidence: non-functional StAR mutants cannot promote the
      cholesterol-to-pregnenolone conversion.
    action: ACCEPT
    reason: >-
      Core molecular function; StAR mutations that abolish steroidogenesis
      establish the transfer activity as essential.
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: regulatory protein, which enhances the mitochondrial conversion of cholesterol
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:12530629
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly demonstrated: only OMM-immobilized StAR constructs were active,
      establishing the outer membrane as its site of action.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: matrix side of the IMM. Only the constructs at the OMM were active
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:17433772
  qualifier: is_active_in
  review:
    summary: >-
      Experimental is_active_in annotation confirming StAR acts exclusively on
      the mitochondrial outer membrane.
    action: ACCEPT
    reason: >-
      Consistent with the biophysical and cell-biology evidence that StAR acts
      only at the outer membrane; core functional localization.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: outer to inner mitochondrial membrane, but acts exclusively on the outer
- term:
    id: GO:0032367
    label: intracellular cholesterol transport
  evidence_type: EXP
  original_reference_id: PMID:17433772
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation for intracellular cholesterol transport; StAR
      moves large amounts of cholesterol from the outer to the inner
      mitochondrial membrane.
    action: ACCEPT
    reason: >-
      Core biological process, directly supported by cell-biology experiments.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: biology experiments show that StAR moves large amounts of cholesterol from the
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: EXP
  original_reference_id: PMID:17433772
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for cholesterol transfer activity; StAR transfers
      cholesterol between membranes (demonstrated in vitro between liposomes and
      in cells between the mitochondrial membranes).
    action: ACCEPT
    reason: >-
      Core molecular function, well supported. This transfer activity, not any
      enzymatic reaction, is StAR's defining biochemical role.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: StAR can transfer cholesterol between synthetic liposomes in
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: EXP
  original_reference_id: PMID:7892608
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation for glucocorticoid biosynthesis based on human
      loss-of-function: StAR mutations impair synthesis of all adrenal steroids,
      including glucocorticoids.
    action: ACCEPT
    reason: >-
      StAR is indispensable for adrenal steroidogenesis; its loss causes
      glucocorticoid (and mineralocorticoid) deficiency in lipoid CAH.
    supported_by:
    - reference_id: PMID:7892608
      supporting_text: that this protein is indispensable normal adrenal and gonadal steroidogenesis.
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196126
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: >-
      The generic molecular carrier activity should be replaced by the specific
      cholesterol transfer activity, which precisely describes StAR's molecular
      function.
    proposed_replacement_terms:
    - id: GO:0120020
      label: cholesterol transfer activity
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: StAR can transfer cholesterol between synthetic liposomes in
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics localization of StAR to the mitochondrion,
      consistent with its established mitochondrial localization.
    action: ACCEPT
    reason: >-
      StAR is a bona fide mitochondrial protein; the high-confidence
      mitochondrial proteome supports this general localization (a more specific
      outer-membrane term is separately annotated experimentally).
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: high-confidence human mitochondrial proteome
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838081
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation placing StAR in the mitochondrial matrix, in
      the context of LONP1-mediated degradation of matrix proteins. This
      reflects that matrix-imported StAR is a substrate for matrix proteases,
      not that the matrix is its functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Localization to the matrix is real (StAR is imported and turned over
      there) but non-core; its site of action is the outer membrane.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838093
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to the mitochondrial matrix in the context
      of LONP1 binding matrix proteins. Same rationale: matrix-imported StAR is
      a protease substrate; the matrix is not its functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but non-core localization; StAR functions at the outer membrane, not
      in the matrix.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839105
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to the mitochondrial matrix in the context
      of AFG3L2 degrading matrix proteins. Reflects matrix protein turnover, not
      the site of StAR activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but non-core localization; StAR's functional site is the outer
      membrane.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839149
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to the mitochondrial matrix in the context
      of AFG3L2 binding matrix proteins. Same rationale as the other matrix
      degradation modules.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but non-core localization; StAR is functional at the outer membrane,
      not the matrix.
    supported_by:
    - reference_id: PMID:12530629
      supporting_text: only on the OMM, providing an unusual example of a protein that exerts its
- term:
    id: GO:0015485
    label: cholesterol binding
  evidence_type: IDA
  original_reference_id: PMID:18403318
  qualifier: enables
  review:
    summary: >-
      IDA annotation for cholesterol binding. The cited paper primarily
      characterizes the paralog StarD4, but explicitly states that StarD1 (STAR)
      is an established cholesterol-binding START domain protein used as the
      comparison standard, and cholesterol binding is directly demonstrated for
      StAR by many sources.
    action: ACCEPT
    reason: >-
      Cholesterol binding is a well-established core molecular function of StAR;
      the supporting text directly names StarD1 as a cholesterol-binding START
      protein. Retained as core.
    supported_by:
    - reference_id: PMID:18403318
      supporting_text: of the cholesterol binding START domain proteins StarD1 and StarD5.
- term:
    id: GO:0070859
    label: positive regulation of bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18403318
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation for positive regulation of bile acid biosynthesis. However,
      the cited study demonstrates this phenotype for the paralog StarD4 (StarD4
      overexpression in hepatocytes increased bile acid synthesis), not for
      STAR/StARD1. STAR is not an established regulator of hepatic bile acid
      biosynthesis and is expressed in steroidogenic tissues, not liver.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The bile-acid biosynthesis phenotype in this paper is a StarD4 property;
      the abstract attributes the increased bile acid synthesis to StarD4
      overexpression in hepatocytes, not to STAR. Following the policy against
      REMOVE of experimental annotations whose full text is not verifiable, this
      is flagged as over-annotated rather than removed; it is not a core StAR
      function.
    supported_by:
    - reference_id: PMID:18403318
      supporting_text: the rates of bile acid synthesis.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196126
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to the mitochondrial intermembrane space, in
      the model of StAR delivering cholesterol from the outer toward the inner
      membrane. StAR necessarily traverses/works across the intermembrane space
      during cholesterol delivery.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with StAR moving cholesterol across the intermembrane space
      toward the inner membrane; retained as a supporting (non-core)
      localization, with the outer membrane as the primary functional site.
    supported_by:
    - reference_id: PMID:17433772
      supporting_text: outer to inner mitochondrial membrane, but acts exclusively on the outer
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:7761400
  qualifier: involved_in
  review:
    summary: >-
      Traceable author statement placing StAR in steroid biosynthesis. Supported
      by the original functional demonstration that StAR increases pregnenolone
      synthesis in reconstituted steroidogenic cells.
    action: ACCEPT
    reason: >-
      Core process role; StAR is required for the initiation of steroid
      biosynthesis by delivering cholesterol to CYP11A1.
    supported_by:
    - reference_id: PMID:7761400
      supporting_text: in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone
core_functions:
- description: >-
    Cholesterol transfer at the mitochondrial outer membrane: StAR binds
    cholesterol in its START domain and delivers it from the outer to the inner
    mitochondrial membrane, the rate-limiting acute step of steroidogenesis.
  molecular_function:
    id: GO:0120020
    label: cholesterol transfer activity
  directly_involved_in:
  - id: GO:0030301
    label: cholesterol transport
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:17433772
    supporting_text: outer to inner mitochondrial membrane, but acts exclusively on the outer
  - reference_id: PMID:12530629
    supporting_text: matrix side of the IMM. Only the constructs at the OMM were active
- description: >-
    Cholesterol binding: the START domain of StAR sequesters a single
    cholesterol molecule, the biochemical basis for its transfer function.
  molecular_function:
    id: GO:0015485
    label: cholesterol binding
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:18403318
    supporting_text: of the cholesterol binding START domain proteins StarD1 and StarD5.
- description: >-
    Acute regulation of steroid hormone biosynthesis: by controlling the
    rate-limiting delivery of cholesterol into mitochondria, StAR abundance sets
    the pace of adrenal and gonadal steroid (pregnenolone and downstream steroid
    hormone) output.
  molecular_function:
    id: GO:0120020
    label: cholesterol transfer activity
  directly_involved_in:
  - id: GO:0050810
    label: regulation of steroid biosynthetic process
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  - id: GO:0005739
    label: mitochondrion
  supported_by:
  - reference_id: PMID:7892608
    supporting_text: that this protein is indispensable normal adrenal and gonadal steroidogenesis.
  - reference_id: PMID:7761400
    supporting_text: in COS-1 cells with cytochrome P450scc and adrenodoxin, increased pregnenolone
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    How is StAR's transient outer-membrane residence and rapid matrix import/
    degradation coupled to the minute-scale acute regulation of steroid output?
suggested_experiments:
- description: >-
    Reconstitute StAR-mediated cholesterol transfer with defined outer-membrane
    proteins to define the minimal functional transfer machinery.
- description: >-
    Systematically test whether any curated StAR protein-protein interactions
    (IntAct) modulate cholesterol transfer or steroidogenic output.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: file:human/STAR/STAR-uniprot.txt
  title: UniProtKB entry STAR_HUMAN (P49675)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record; FUNCTION, CATALYTIC ACTIVITY (cholesterol transport
      reaction), PATHWAY and SUBCELLULAR LOCATION statements used as supporting
      text.
- id: PMID:12530629
  title: The steroidogenic acute regulatory protein, StAR, works only at the outer
    mitochondrial membrane.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes that StAR acts only at the outer mitochondrial membrane despite
      being targeted to the matrix; source for OMM site-of-action and matrix
      non-core localization.
- id: PMID:17433772
  title: Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol
    transporter.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Review establishing StAR's cholesterol transfer activity and exclusive
      action on the outer membrane; supports MF and transport annotations.
- id: PMID:18403318
  title: Intracellular cholesterol transporter StarD4 binds free cholesterol and increases
    cholesteryl ester formation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: >-
      Primarily a StarD4 (paralog) paper. It names StarD1/STAR only as the
      reference cholesterol-binding START protein, which supports the STAR
      cholesterol-binding IDA. Its bile-acid biosynthesis phenotype is a StarD4
      property and does not support the STAR bile-acid regulation annotation
      (flagged over-annotated).
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale interactome; source of an uninformative StAR protein-binding
      IPI (MAGEA11). No functional relevance established.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Systematic interactome study; source of an uninformative StAR
      protein-binding IPI.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Alternative-splicing interactome; source of an uninformative StAR
      protein-binding IPI.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference interactome; source of several uninformative StAR
      protein-binding IPIs.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Neurodegenerative-disease interactome; source of an uninformative StAR
      protein-binding IPI (HTT).
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-confidence mitochondrial proteome (MitoCoP); supports the HTP
      mitochondrion localization.
- id: PMID:7761400
  title: 'Human steroidogenic acute regulatory protein: functional activity in COS-1
    cells, tissue-specific expression, and mapping of the structural gene to 8p11.2
    and a pseudogene to chromosome 13.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original human StAR functional characterization: >4-fold increase in
      pregnenolone with P450scc/adrenodoxin; tissue expression; gene mapping.
- id: PMID:7892608
  title: Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human loss-of-function (lipoid CAH) evidence that StAR is indispensable for
      adrenal and gonadal steroidogenesis.
- id: Reactome:R-HSA-196108
  title: Pregnenolone biosynthesis
  findings: []
- id: Reactome:R-HSA-196126
  title: STAR mediates CHOL translocation from cytosol to mitochondrial intermembrane
    space
  findings: []
- id: Reactome:R-HSA-9838081
  title: LONP1 degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838093
  title: LONP1 binds mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9839105
  title: AFG3L2 degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9839149
  title: AFG3L2 binds mitochondrial matrix proteins
  findings: []

Gene Description

Existing Annotations Review

Core Functions

Cholesterol transfer at the mitochondrial outer membrane: StAR binds cholesterol in its START domain and delivers it from the outer to the inner mitochondrial membrane, the rate-limiting acute step of steroidogenesis.

Cholesterol binding: the START domain of StAR sequesters a single cholesterol molecule, the biochemical basis for its transfer function.

Acute regulation of steroid hormone biosynthesis: by controlling the rate-limiting delivery of cholesterol into mitochondria, StAR abundance sets the pace of adrenal and gonadal steroid (pregnenolone and downstream steroid hormone) output.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

STAR (Steroidogenic acute regulatory protein, StAR / StARD1) — review notes

Deep research status

Core biology

Localization / mechanism

Tissue / disease

Function / activity evidence

Annotation-specific caveats

Core functions (for review)

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