From scarcity to abundance: Adaptive strategies in adenosine triphosphate-binding cassette transporter function

Adenosine triphosphate-binding cassette (ABC) transporters form one of the most ancient and functionally diverse protein superfamilies, mediating the translocation of substrates that span an expansive range of sizes, chemistries, and physiological roles. This diversity poses a challenge to unifying their mechanisms within a single conceptual framework. In this review, we examine recent advances that demonstrate how substrate properties, energetic constraints, and evolutionary pressures shape the molecular design and operating principles of ABC transporters. We discuss emerging insights into substrate recognition and selectivity in exporters and importers, revisit the physiological relevance of so-called 'futile' adenosine triphosphate (ATP) hydrolysis, and explore the role of stoichiometry as a regulatory and evolutionary variable. Together, these perspectives highlight common design principles that link molecular architecture to the functional demands of transport across the ABC family, offering broader insights for how protein systems adapt structure and energetics to diverse cellular challenges.