Bend it like BIN1: how a membrane-curving adaptor protein shapes cardiac physiology

Bridging integrator 1, initially named box-dependent myc-interacting protein-1 (BIN1), and also known as Amphiphysin 2 is a versatile N-BAR protein that plays essential roles in membrane remodeling, protein trafficking, and cellular organization across multiple tissues. Although extensively studied in cancer and Alzheimer's disease, BIN1's critical functions in cardiac physiology and pathology represent an emerging frontier with significant therapeutic implications. This review provides a synopsis of our current understanding of BIN1's structure-function relationships, with particular emphasis on cardiac-specific isoforms and their roles in heart function. We examine how BIN1's various domains-including the membrane-curvature forming and sensing BAR domain, phosphoinositide-binding motif, and SH3 protein-protein interaction domains-orchestrate its diverse cellular functions, from t-tubule growth, microfolding, and anchoring to directed protein trafficking and complex assembly. Recent discoveries highlight BIN1's involvement in cardiac aging and disease, where both deficiency and excess of BIN1 can lead to dysfunction. Notably, BIN1 levels are reduced in heart failure while increasing significantly during cardiac aging, suggesting a bidirectional pathophysiology where both insufficient and excessive BIN1 expression can impair cardiac function. We discuss emerging evidence regarding the role of BIN1 in cardiac pathologies, offering potential therapeutic targets. Understanding BIN1's membrane-shaping capabilities and its roles in organizing excitation-contraction coupling machinery could yield novel therapeutic strategies for addressing cardiac dysfunction in various disease contexts.