Summary Abstract: Protein Networks as Synergistic Drivers of Membrane Remodeling
Membrane curvature is required for many cellular processes, from assembly of highly curved trafficking vesicles
to extension of needle-like filopodia. Consequently, defects in membrane curvature play a role in most human
diseases, including altered recycling of receptors in cancer and diabetes, targeting of filopodia by pathogens,
and hijacking of vesicle traffic during virus replication. Therefore, understanding the basic molecular mechanisms
that drive membrane remodeling is essential to our knowledge of cellular physiology and human disease.
Research on membrane curvature has primarily focused on individual protein domains with specialized
structures, such as crescent-shaped scaffolds and wedge-like amphipathic insertions. While this work has
provided invaluable insights, this “structure-centric” perspective ignores two essential facts. First, most
membrane remodeling proteins contain large intrinsically disordered domains in addition to structured domains.
And second these disordered domains drive assembly of large, multi-valent protein networks.
During the past 5 years, our group has made pioneering discoveries in support of the hypothesis
that disordered protein networks are essential drivers of membrane remodeling in the cell. Specifically,
using clathrin-mediated endocytosis as a model pathway, we showed that intrinsically disordered domains
generate steric pressure at membrane surfaces. This pressure provides a surprisingly potent driving force for
membrane bending, especially when coupled synergistically to the contributions of structured domains. This
work was the first to reveal the membrane remodeling abilities of disordered proteins, examples of which have
since been discovered in diverse areas of biology. Additionally, we have recently found that disordered domains
within endocytic proteins drive assembly of liquid-like protein networks which efficiently initiate endocytosis.
Importantly, this liquid-like behavior has the potential to resolve a long-standing paradox by explaining how
curved membrane structures can be simultaneously highly interconnected, yet dynamic and flexible.
These findings suggest urgent questions about the role of disordered protein networks in the key steps
of membrane remodeling: (i) initiation, (ii) curvature induction, and (iii) cargo selection. First, how do protein
networks initiate remodeling events, controlling their spatial and temporal dynamics? Second, once an event is
initiated, how do protein networks bend membranes, stabilizing either a convex or a concave shape? Third, as
the membrane bends, how does the protein network select cargo, such as transmembrane proteins, which are
essential to the structure’s biological function? Building on our recent discoveries, this work will shift the paradigm
for understanding membrane curvature beyond its present focus on in vitro structure-function relationships
toward an understanding of disordered protein networks. By demonstrating novel synergistic mechanisms, this
research will provide a blueprint for the study of protein networks at membrane surfaces throughout the cell.