ABCG2 Protein
Overview <table class="infobox infobox-protein">Gene </td>UniProt </td>PDB Structures </td>Molecular Weight </td>Subcellular Localization </td>Protein Family </td>Length </td>
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ABCG2 Protein
Overview <table class="infobox infobox-protein">Gene </td>UniProt </td>PDB Structures </td>Molecular Weight </td>Subcellular Localization </td>Protein Family </td>Length </td>
ABCG2 (ATP-binding cassette subfamily G member 2), also known as BCRP (Breast Cancer Resistance Protein), is a multidrug resistance transporter expressed at high levels in the [blood-brain barrier](/entities/blood-brain-barrier) (BBB), liver, intestine, and hematopoietic stem cells[@schinkel2022]. It plays a critical role in protecting the brain from xenobiotics and is a key determinant of drug delivery to the CNS. ABCG2 functions as a half-transporter, forming homodimers to create functional efflux pumps.
In the context of neurodegenerative diseases, ABCG2 has been implicated in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and brain tumor drug resistance. The transporter's expression and function at the BBB make it a critical determinant of CNS drug penetration for therapeutics targeting neurodegenerative conditions.
Protein Infobox
Structure ABCG2 has characteristic ABCG family architecture[@schinkel2022]:
Transmembrane Domain
Single transmembrane domain: Six α-helicesNucleotide-binding domain: Located at the N-terminus (unusual for ABCG family)Membrane topology: N-terminus extracellular, C-terminus intracellularNucleotide-Binding Domain
Walker A motif: P-loop for ATP bindingWalker B motif: Coordinates Mg²⁺ABC signature: C-loop (LSGGQ)H-loop: Catalytic histidineOligomerization
Functional form: HomodimerDimerization: C-terminal interactionsQuaternary structure: Two monomers form functional transporterStructural Comparison
ABCG1: Cholesterol efflux, liver expressionABCG4: Brain-specific expressionABCG8: Cholesterol transport, intestineNormal Function
Blood-Brain Barrier Protection ABCG2 is a major efflux transporter at the BBB[@zhou2023]:
Protective Function
Xenobiotic efflux: Pumps toxins out of brain capillariesDrug efflux: Limits CNS penetration of many drugsMaintains CNS homeostasis: Protects against dietary toxinsCellular Localization
Apical membrane: Luminal side of brain endothelial cellsCo-localizes: With P-glycoprotein (ABCB1)Synergistic protection: Multiple efflux transportersStem Cell Protection ABCG2 maintains hematopoietic stem cell function[@wang2019]:
Stem cell quiescence: High expression in primitive HSCsToxin protection: Chemotherapy resistanceStress response: Protects against oxidative stressIntestinal Barrier In the intestine, ABCG2:
Limits oral drug absorption
Protects against dietary toxins
Affects bioavailability
Drug Resistance In cancer, ABCG2 contributes to multidrug resistance[@ahmad2018]:
Chemotherapy efflux
Reduced drug accumulation
Treatment failure in brain tumors
Role in Neurodegeneration
Alzheimer's Disease ABCG2 is altered in AD and affects disease progression[@vlaming2018]:
Expression Changes
ABCG2 expression altered at the BBB in AD
Reduced function may affect Aβ clearance
Potential therapeutic target
Aβ Transport
May be involved in Aβ transport across the BBB
Altered function affects amyloid pathology
Therapeutic modulation in development
Drug Delivery
Limits CNS penetration of AD therapeutics
Considerations for drug design
Combination approaches with BBB disruption
Parkinson's Disease ABCG2 affects PD vulnerability and treatment[@jang2015]:
Dopaminergic Vulnerability
Reduced ABCG2 function may contribute to dopaminergic neuron vulnerability
MPP+ (PD toxin) is an ABCG2 substrate
May affect toxin clearance from substantia nigra
Therapeutic Implications
ABCG2 polymorphisms affect drug delivery to brain
L-dopa penetration affected
Considerations for PD drug development
Brain Tumors ABCG2 contributes to treatment resistance[@ahmad2018]:
Glioblastoma: Limits chemotherapeutic efficacyMedulloblastoma: Therapeutic challengeMetastatic brain tumors: Multi-drug resistanceNeuroinflammation ABCG2 may be affected in neuroinflammatory conditions:
Expression modulated by cytokines
May affect inflammatory mediator clearance
Role in neurovascular unit function
Therapeutic Targeting
Enhancing CNS Drug Delivery Strategies to overcome ABCG2-mediated efflux[@nies2017]:
Inhibitors
Ko143: Potent ABCG2 inhibitor (research use)Fumitremorgin C: Natural product inhibitorNovel inhibitors: In development for clinical useCombination Approaches
Co-administration with inhibitors
Nanoparticle formulations
Prodrug strategies
Considerations
Toxicity: ABCG2 has protective functionsPeripheral effects: May affect chemotherapy efficacyTiming: Therapeutic windowsGenetic Considerations ABCG2 polymorphisms affect drug response[@cheng2021]:
Q141K variant: Reduced function, affects drug pharmacokineticsClinical implications: Individualized dosingDrug interactions: Substrate competitionABCG2 Polymorphisms in Disease
Neurological disease associations: Being investigatedTreatment response: Predictive biomarker potentialPharmacogenomics: Clinical implementationKey Publications
[Vlaming ML, et al, ABCG2 in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29689089/)
[Jang M, et al, ABCG2 in Parkinson's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26227554/)
[Nies AT, et al, ABCG2 and CNS drug delivery (2017)](https://pubmed.ncbi.nlm.nih.gov/28755984/)
[Schinkel AH, et al, ABCG2 transporter function and expression (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)
[Zhou L, et al, ABCG2 and blood-brain barrier function (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)
[Kisler BR, et al, ABCG2 in the neurovascular unit (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Cheng Z, et al, ABCG2 polymorphisms and neurological disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34127088/)
[Wang J, et al, ABCG2 in stem cell biology and neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31791321/)
[Ahmad A, et al, ABCG2 and drug resistance in brain tumors (2018)](https://pubmed.ncbi.nlm.nih.gov/29218543/)
[Mittapalli RK, et al, Role of ABCG2 in CNS pharmacotherapy (2017)](https://pubmed.ncbi.nlm.nih.gov/28417642/)
Cross-Links
[ABCG2 Gene](/genes/abcg2) - Gene page
[Blood-Brain Barrier](/entities/blood-brain-barrier) - Key site
[Alzheimer's Disease](/diseases/alzheimers-disease) - Disease
[Parkinson's Disease](/diseases/parkinsons-disease) - Disease
[Multidrug Resistance](/mechanisms/multidrug-resistance) - Mechanism
References
[Vlaming ML, et al, ABCG2 in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29689089/)
[Jang M, et al, ABCG2 in Parkinson's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26227554/)
[Nies AT, et al, ABCG2 and CNS drug delivery (2017)](https://pubmed.ncbi.nlm.nih.gov/28755984/)
[Schinkel AH, et al, ABCG2 transporter function and expression (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)
[Zhou L, et al, ABCG2 and blood-brain barrier function (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)
[Kisler BR, et al, ABCG2 in the neurovascular unit (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Cheng Z, et al, ABCG2 polymorphisms and neurological disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34127088/)
[Wang J, et al, ABCG2 in stem cell biology and neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31791321/)
[Ahmad A, et al, ABCG2 and drug resistance in brain tumors (2018)](https://pubmed.ncbi.nlm.nih.gov/29218543/)
[Mittapalli RK, et al, Role of ABCG2 in CNS pharmacotherapy (2017)](https://pubmed.ncbi.nlm.nih.gov/28417642/)
See Also
[ABCG2 Gene](/genes/abcg2)
[Blood-Brain Barrier](/entities/blood-brain-barrier)
[Pharmacokinetics in Neurodegeneration](/mechanisms/cns-drug-delivery)
[Multidrug Resistance](/mechanisms/multidrug-resistance)
[Neurovascular Unit](/entities/neurovascular-unit)
External Links
[UniProt: Q9UN50](https://www.uniprot.org/uniprot/Q9UN50)
[GeneCards: ABCG2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCG2)
[PDB: ABCG2 structure](https://www.rcsb.org/structure/6VXF)
[PharmGKB: ABCG2 polymorphisms](https://www.pharmgkb.org/)
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