ABC proteins as drivers of paradigm shifts: The transformative roles of MDR1 and ABCA1 in cell biology

Research on ATP-binding cassette (ABC) proteins has sparked several paradigm shifts in cell biology. MDR1, the first eukaryotic ABC protein identified in 1986, overturned the long-held belief that lipophilic compounds cross cell membranes solely via simple diffusion. By actively transporting these substances, MDR1 protects vital organs from environmental toxins and mediates complex drug-drug interactions. Its mechanism of action, revealed through structural biology, differs fundamentally from the specific substrate recognition typically seen in enzymes. Similarly, ABCA1 has transformed our understanding of the physiological significance of cholesterol. Beyond its role in HDL generation, ABCA1 translocates cholesterol from the inner to the outer leaflet of the plasma membrane, establishing a critical concentration gradient. Studies using high-speed atomic force microscopy (HS-AFM) have uncovered a mechanism for nascent HDL production that challenges conventional models of protein function. This review highlights how these two ABC proteins, MDR1 and ABCA1, have redefined biological transport and physiological homeostasis, driving major shifts in the field.