ABCA7 - ATP Binding Cassette Transporter A7 | Elisa - Clia - Antibody - Protein

Background

ABCA7 (ATP-binding cassette subfamily A member 7) is a member of the ABC transporter family, which is responsible for the translocation of various substrates across membranes in an ATP-dependent manner. ABCA7 is primarily known for its role in lipid homeostasis and phagocytosis, and its genetic associations with neurodegenerative diseases, particularly Alzheimer's disease, have attracted significant scientific interest.

ABCA7 is expressed in various tissues, including the brain, liver, spleen, and bone marrow, with particularly high levels in the central nervous system and immune cells. This distribution suggests its dual role in maintaining neuronal integrity and immune responses. ABCA7's function is closely related to lipid transport, particularly in regulating cellular cholesterol and phospholipid efflux. Emerging evidence also indicates its involvement in amyloid precursor protein (APP) processing and amyloid-beta peptide clearance, key mechanisms in Alzheimer's pathology.

The gene encoding ABCA7, located on chromosome 19p13.3, has been a focus of genetic studies, revealing that mutations and polymorphisms can influence susceptibility to Alzheimer’s disease. Beyond neurodegeneration, ABCA7 may also play roles in immune regulation, inflammation, and other lipid-related disorders.

Protein Structure

Primary Structure:

• ABCA7 consists of 2,146 amino acids and has a molecular weight of approximately 220 kDa.
• It is encoded by the ABCA7 gene located on chromosome 19p13.3.
• The sequence contains two nucleotide-binding domains (NBDs), which are critical for ATP hydrolysis and energy transduction, and two transmembrane domains (TMDs), which form the substrate transport pathway.

Domain Organization:

• Nucleotide-Binding Domains (NBDs):
• ABCA7 has two conserved NBDs containing Walker A, Walker B, and the ABC signature motif.
• These domains are responsible for binding and hydrolyzing ATP, driving the transport cycle.
• Transmembrane Domains (TMDs):
• The protein contains 12 transmembrane helices distributed across its two TMD regions.
• These helices form the substrate-binding cavity, facilitating the translocation of lipids such as cholesterol and phospholipids.
• Regulatory Regions:
• ABCA7 features long intracellular and extracellular loops that may mediate interactions with regulatory proteins or lipids.

Structural Insights:

• The overall architecture of ABCA7 closely resembles that of other ABCA family members, such as ABCA1, which is involved in high-density lipoprotein (HDL) formation.
• The protein undergoes conformational changes during the ATP hydrolysis cycle, alternating between inward-facing and outward-facing conformations to transport substrates.

Post-Translational Modifications:

• Glycosylation: ABCA7 has extracellular glycosylation sites that may influence stability and activity.
• Phosphorylation: Cytoplasmic phosphorylation sites may regulate ABCA7 activity in response to cellular signals.

Localization:

• ABCA7 is a plasma membrane protein but is also found in intracellular compartments such as endosomes and the endoplasmic reticulum.

Classification and Subtypes

Classification:

• ABCA7 is a member of the ABCA subfamily, which primarily transports lipids and lipid-related molecules.
• It is most closely related to ABCA1, another key regulator of lipid metabolism and HDL formation.

Subtypes:

• ABCA7 does not have defined subtypes, but genetic polymorphisms and splice variants may influence its function and disease associations.

Function and Biological Significance

Lipid Transport:

• ABCA7 facilitates the efflux of cholesterol and phospholipids to apolipoproteins, contributing to lipid homeostasis and HDL formation.
• It plays a role in maintaining cellular membrane composition, particularly in neurons and immune cells.

Phagocytosis:

• ABCA7 is involved in the clearance of apoptotic cells and debris through phagocytosis.
• It is highly expressed in macrophages, where it enhances engulfment of dead cells, contributing to tissue homeostasis and immune regulation.

Role in Alzheimer’s Disease:

• ABCA7 influences the processing and clearance of amyloid-beta, a key protein in Alzheimer’s pathology.
• Loss-of-function mutations in ABCA7 are associated with reduced amyloid clearance, leading to plaque accumulation.

Immune System Regulation:

• ABCA7 modulates inflammatory responses by regulating lipid-mediated signaling pathways in immune cells such as macrophages and microglia.

Neuroprotection:

• In the brain, ABCA7 supports neuronal survival by maintaining lipid balance and removing amyloidogenic proteins.

Cholesterol Homeostasis:

• ABCA7 plays a role in cholesterol export, which is crucial for maintaining membrane fluidity and signaling.

Clinical Issues

Neurodegenerative Diseases:

• Alzheimer’s Disease:
• Genetic variants in ABCA7 are strongly associated with an increased risk of late-onset Alzheimer’s disease.
• Mutations may impair amyloid-beta clearance, promoting plaque deposition and neuroinflammation.
• Mechanisms:
• Reduced ABCA7 expression correlates with defective phagocytosis, lipid imbalance, and increased neuronal vulnerability.

Cardiovascular Diseases:

• Although less studied, ABCA7's role in lipid metabolism suggests potential implications in atherosclerosis and cardiovascular conditions.

Cancer:

• Dysregulated ABCA7 expression has been observed in certain cancers, suggesting a possible role in tumor progression or lipid signaling.

Rare Genetic Disorders:

• Loss-of-function mutations or SNPs in ABCA7 can lead to lipid metabolism disorders or exacerbate neuroinflammatory conditions.

Summary

ABCA7 is a critical member of the ATP-binding cassette family, primarily involved in lipid transport, phagocytosis, and neuroprotection. Structurally, it features conserved nucleotide-binding and transmembrane domains that drive ATP-dependent substrate transport. Functionally, ABCA7 plays a vital role in lipid homeostasis, immune responses, and the clearance of amyloid-beta, positioning it as a significant player in neurodegenerative diseases like Alzheimer’s.

• Clinically, ABCA7 mutations or dysregulation are associated with Alzheimer’s disease and potentially other conditions like cardiovascular diseases and cancer. Its dual role in lipid metabolism and immune regulation underscores its importance in maintaining cellular and tissue integrity. As research progresses, ABCA7 continues to be a promising target for therapeutic intervention in neurodegenerative and lipid-related disorders.
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