An ABC transporter is a protein that sits in a cell’s membrane and uses energy from ATP (the cell’s universal fuel molecule) to pump substances in or out. The name stands for “ATP-binding cassette,” referring to the energy-powered engine that drives each transporter. Humans have 48 of these transporters, and they show up in every form of life, from bacteria to plants to animals. They move an enormous range of cargo: fats, cholesterol, waste products, toxins, and drugs.
How the Transporter Is Built
Every ABC transporter shares the same basic blueprint: four functional units working together. Two of these are transmembrane domains, which form a channel-like structure that spans the cell membrane. Each transmembrane domain contains 6 to 10 spiral-shaped protein segments that thread back and forth through the membrane, creating a path for cargo to cross. The other two units are nucleotide-binding domains, which sit inside the cell and act as the engine. These are the parts that grab ATP and break it apart to generate the energy needed for transport.
In bacteria, these four units are often separate protein pieces that assemble together. In human cells, most ABC transporters are a single large protein containing all four units in one chain. Some are built from two identical halves that pair up, while others combine two different halves.
How Cargo Gets Moved
ABC transporters work by flipping between two shapes. In one shape, the channel opens toward the inside of the cell. In the other, it opens toward the outside. When two ATP molecules bind to the engine domains, they clamp together tightly, which forces the channel portion to switch from inward-facing to outward-facing. This mechanical shift pushes whatever cargo is sitting in the channel out of the cell.
Once the cargo is released, the ATP molecules are broken down into ADP and a free phosphate group through a three-step chemical reaction. This breakdown loosens the engine domains, letting the transporter spring back to its original inward-facing shape, ready to grab the next piece of cargo. Interestingly, the energy released by breaking ATP doesn’t directly “push” the cargo. Instead, ATP binding is what triggers the shape change, and ATP breakdown simply resets the transporter for the next cycle.
In bacteria, ABC transporters can work in both directions. Some import nutrients like sugars and amino acids from the environment into the cell. Others act as efflux pumps, pushing toxic compounds out. In human cells, ABC transporters function almost exclusively as exporters, moving substances from the inside of the cell to the outside or into internal compartments like lysosomes and mitochondria.
The Seven Human Subfamilies
The 48 human ABC transporters are organized into seven subfamilies labeled A through G, based on how similar their protein sequences are to one another. Each subfamily tends to handle a different type of job.
- Subfamily A includes transporters involved in moving lipids. ABCA1, one of the most studied members, plays a central role in cholesterol metabolism.
- Subfamily B contains P-glycoprotein (ABCB1), the first ABC transporter discovered to pump drugs out of cells. Other members in this group localize to mitochondria and handle iron metabolism.
- Subfamily C is one of the largest, with 12 members. It includes ion channel regulators, drug-resistance proteins, and the CFTR protein involved in cystic fibrosis.
- Subfamily D transporters operate in peroxisomes, small compartments inside cells that break down fatty acids.
- Subfamily E and F members lack the transmembrane channel portions and don’t transport molecules across membranes at all. Instead, they participate in protein synthesis and gene regulation inside the cell.
- Subfamily G contains six “reverse” half transporters with an unusual structure where the engine domain sits at the front of the protein rather than the back. ABCG2, also called breast cancer resistance protein, is a key drug-efflux pump in this group.
Cholesterol and Heart Disease
Two ABC transporters, ABCA1 and ABCG1, are responsible for the bulk of cholesterol removal from a type of immune cell called a macrophage. Macrophages can gorge on cholesterol and become “foam cells,” which accumulate in artery walls and drive atherosclerosis. ABCA1 and ABCG1 together account for roughly 70% of the cholesterol that loaded macrophages can offload.
ABCA1 hands cholesterol off to a protein carrier called apoA-I, which is the starting material for HDL (often called “good cholesterol”). ABCG1 is less picky and can transfer cholesterol to HDL, LDL, and other acceptors without needing to physically bind them. When both transporters are knocked out in animal studies, macrophages become massively engorged with cholesterol and atherosclerosis accelerates dramatically. Beyond cholesterol removal, these transporters also influence how the cell membrane is organized, which affects inflammatory signaling. ABCG1 in particular appears to dampen macrophage inflammatory responses by reshaping the lipid composition of the outer membrane.
Cancer Drug Resistance
One of the most clinically significant roles of ABC transporters is their ability to make cancer cells resistant to chemotherapy. When tumor cells ramp up production of certain ABC transporters, those proteins act as pumps that eject chemotherapy drugs before they can do their job. This phenomenon, called multidrug resistance, is a major reason why initially effective cancer treatments stop working.
Three transporters are the primary culprits. P-glycoprotein (ABCB1) was the first identified and handles the broadest range of drugs, including common chemotherapy agents like doxorubicin, paclitaxel, vincristine, and methotrexate. MRP1 (ABCC1) overlaps with P-glycoprotein but specializes in pumping out drugs that have been chemically tagged by the cell for disposal. BCRP (ABCG2) rounds out the trio with its own wide substrate range.
A meta-analysis of 31 clinical studies found that P-glycoprotein was present in 41% of breast tumors, and patients whose tumors expressed it were three times more likely to fail chemotherapy. Even a brief exposure to a drug like doxorubicin can trigger tumor cells to rapidly increase P-glycoprotein production, creating acquired resistance during the course of treatment.
Guarding the Blood-Brain Barrier
The blood-brain barrier is lined with cells that tightly control what enters the brain from the bloodstream. ABC transporters are a major part of that defense. P-glycoprotein and BCRP are both highly expressed on the blood-facing surface of brain capillary cells, where they work together to pump drugs and toxins back into the bloodstream before they can reach brain tissue.
This is a double-edged sword. It protects the brain from harmful substances, but it also blocks many therapeutic drugs from reaching brain tumors, infections, or neurodegenerative disease targets. Designing drugs that can slip past these gatekeepers, or temporarily inhibiting the transporters to allow drug delivery, is an active area of pharmaceutical development. Other family members like MRP1 and MRP4 are positioned on the brain-facing side of barrier cells, adding another layer of complexity to how drugs move in and out of the central nervous system.
Cystic Fibrosis: When an ABC Transporter Becomes a Channel
CFTR (ABCC7) is one of the most unusual ABC transporters in the human body. Instead of pumping large molecules across a membrane, it functions as an ion channel that allows chloride ions to flow through. Mutations in the gene encoding CFTR cause cystic fibrosis, a disease characterized by thick, sticky mucus in the lungs and digestive tract.
Structurally, CFTR still looks like a typical ABC transporter, with the same engine domains and transmembrane segments. The key difference is a side opening, or lateral portal, between two of its transmembrane extensions. This portal creates a continuous water-filled pathway connecting the inside and outside of the cell. In a normal ABC transporter, cargo is sealed inside the channel and released in one direction. CFTR’s portal short-circuits that design, letting small chloride ions flow freely whenever the channel is in its open state. Researchers believe this portal is how evolution repurposed a pump into a channel, a structural shortcut that allowed a completely different function to emerge from the same protein architecture.