Disordered protein networks as mechanistic drivers of membrane remodeling and endocytosis

Endocytosis is an essential cellular pathway, which is responsible for importing nutrients, recycling receptors, and controlling signaling processes. Research on the molecular mechanisms of endocytosis has traditionally focused on individual protein domains with specialized structures. While this “structure-centric” perspective has provided invaluable insights, it ignores two essential facts. First, most proteins involved in endocytosis contain substantial intrinsically disordered domains. Second, these disordered domains drive assembly of large, multivalent protein networks. During the past decade, multiple labs have made pioneering discoveries suggesting that disordered protein networks are essential drivers of endocytosis. In this review, we present these recent findings as we follow vesicle biogenesis from its early initiation, through membrane curvature, coating, and eventual uncoating. At each step, we point out novel molecular mechanisms that rely on the conformational entropy of intrinsically disordered domains and upon their ability to form flexible, liquid-like networks that catalyze protein assembly.