ABCB - ATP binding cassette subfamily B member|Elisa - Clia - Antibody - Protein

Background

The ATP-binding cassette (ABC) transporters represent a large family of membrane proteins responsible for the active translocation of a wide variety of substrates across cellular membranes. This translocation is powered by ATP hydrolysis, a hallmark of the transporter’s function. The subset of ABC transporters labeled ABCB1 through ABCB11, including ABCB4 through ABCB10, have distinct and overlapping roles in cellular physiology, particularly in drug metabolism, lipid transport, and detoxification processes. Collectively referred to as ABCB transporters, these proteins are critical for maintaining cellular homeostasis by exporting xenobiotics, lipids, and metabolic by-products.

These transporters are ubiquitously expressed, though tissue-specific expression patterns define their functions. They are integral to the blood-brain barrier, hepatobiliary system, and mitochondrial processes. Additionally, dysfunction or dysregulation of ABCB transporters is implicated in various human diseases, including cancer drug resistance, cholestatic liver disease, and mitochondrial disorders.

The genes encoding ABCB proteins are distributed across different chromosomes, with each having specific regulatory sequences that ensure tight transcriptional and translational control. For instance, ABCB1 (also known as P-glycoprotein or MDR1) is well-known for its role in multidrug resistance in cancer therapy, whereas ABCB11 (bile salt export pump or BSEP) is critical in bile acid secretion.

Protein Structure

Primary Structure:

• The ABCB transporter family members are composed of approximately 1,200–1,500 amino acids, with molecular weights ranging between 130–170 kDa.
• The hallmark features include two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs), each containing six alpha-helices.

Domain Organization:

• Nucleotide-Binding Domains (NBDs):
• The NBDs are located in the cytoplasmic portion of the protein and contain conserved motifs such as Walker A, Walker B, and the ABC signature motif.
• ATP binding and hydrolysis occur at these sites, providing the energy required for substrate transport.
• Transmembrane Domains (TMDs):
• The TMDs create a channel-like structure for substrate binding and translocation.
• These regions exhibit substrate specificity through conserved residues that interact with the transported molecules.

Tertiary and Quaternary Structure:

• ABCB proteins form a symmetric dimeric structure, where each monomer contributes one NBD and one TMD, creating a functional transporter.
• Conformational changes driven by ATP hydrolysis alternate between inward-facing and outward-facing orientations to move substrates across the membrane.

Post-Translational Modifications:

• Glycosylation: Many ABCB transporters, such as ABCB1, undergo glycosylation, which stabilizes the protein and modulates function.
• Phosphorylation: Regulatory phosphorylation sites can affect transporter activity in response to cellular signals.

Localization:

• While ABCB1 localizes to the plasma membrane, other family members, such as ABCB10, are found in mitochondrial membranes. ABCB4 and ABCB11 are predominantly expressed in hepatocytes.

Classification and Subtypes

Classification:

• ABCB transporters belong to the larger ABC transporter superfamily and specifically to subfamily B, defined by their structural homology and shared ATPase-dependent function.

Key Members:

• ABCB1: Involved in multidrug resistance and xenobiotic efflux at the blood-brain barrier and intestinal epithelium.
• ABCB4: Facilitates phospholipid transport across the canalicular membrane of hepatocytes.
• ABCB11: Functions as the bile salt export pump in bile secretion.
• ABCB10: Participates in mitochondrial iron-sulfur cluster biosynthesis.
• ABCB7: Mitochondrial transporter involved in iron homeostasis.
• ABCB8 and ABCB9: Involved in mitochondrial and lysosomal peptide transport.

Function and Biological Significance

Xenobiotic Transport:

• ABCB1 efficiently pumps out drugs, toxins, and other xenobiotics, contributing to chemotherapeutic drug resistance in cancer cells.

Lipid Transport:

• ABCB4 plays a pivotal role in hepatobiliary phosphatidylcholine secretion, protecting the bile ducts from bile acid-induced toxicity.
• ABCB11 is responsible for the excretion of bile acids, essential for lipid digestion and cholesterol elimination.

Mitochondrial Function:

• ABCB10 and ABCB7 regulate iron-sulfur cluster assembly and heme biosynthesis, which are critical for mitochondrial respiration and metabolic processes.

Cellular Detoxification:

• ABCB proteins prevent the accumulation of harmful endogenous metabolites and environmental toxins by active efflux.

Barrier Integrity:

• ABCB1 reinforces the integrity of the blood-brain barrier by exporting neurotoxic compounds, maintaining CNS homeostasis.

Clinical Issues

Drug Resistance:

• Overexpression of ABCB1 in tumors leads to multidrug resistance, rendering chemotherapies less effective.
• Strategies targeting ABCB1 have been explored to overcome resistance in cancers such as leukemia and breast cancer.

Cholestatic Liver Disease:

• Mutations in ABCB4 or ABCB11 result in impaired bile phospholipid or bile acid transport, causing progressive familial intrahepatic cholestasis (PFIC) and gallstone disease.

Neurodegeneration:

• Dysfunction of ABCB1 at the blood-brain barrier can exacerbate neurodegenerative conditions such as Alzheimer’s disease by impairing amyloid-beta clearance.

Mitochondrial Disorders:

• Mutations in ABCB7 or ABCB10 are associated with diseases like X-linked sideroblastic anemia and mitochondrial iron-sulfur cluster deficiencies.

Genetic Polymorphisms:

• Variants in ABCB genes influence individual susceptibility to drug toxicities, cholesterol metabolism disorders, and other diseases.

Summary

The ABCB subfamily of ATP-dependent translocases is essential for cellular detoxification, lipid transport, and mitochondrial function. Structurally, these transporters share conserved NBDs and TMDs, forming dimeric channels that actively translocate a diverse array of substrates. ABCB1, known for its role in drug resistance, highlights the clinical relevance of this family, while ABCB4 and ABCB11 are vital in liver function. ABCB7, ABCB8, and ABCB10 underscore the significance of this family in mitochondrial processes. Dysregulation or mutation of ABCB proteins contributes to severe clinical conditions, ranging from cholestasis and neurodegeneration to drug resistance in cancer. These findings affirm the importance of understanding ABCB transporters in both physiology and therapeutic development.