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

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

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