Multivalent interactions between molecular components involved in fast endophilin mediated endocytosis drive protein phase separation

Samsuzzoha Mondal, Karthik Narayan, Samuel Botterbusch, Imania Powers, Jason Zheng, Honey Priya James, Rui Jin and Tobias Baumgart ()
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Samsuzzoha Mondal: University of Pennsylvania
Karthik Narayan: University of Pennsylvania
Samuel Botterbusch: University of Pennsylvania
Imania Powers: University of Pennsylvania
Jason Zheng: University of Pennsylvania
Honey Priya James: University of Pennsylvania
Rui Jin: University of Pennsylvania
Tobias Baumgart: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract A specific group of transmembrane receptors, including the β1-adrenergic receptor (β1-AR), is internalized through a non-clathrin pathway known as Fast Endophilin Mediated Endocytosis (FEME). A key question is: how does the endocytic machinery assemble and how is it modulated by activated receptors during FEME. Here we show that endophilin, a major regulator of FEME, undergoes a phase transition into liquid-like condensates, which facilitates the formation of multi-protein assemblies by enabling the phase partitioning of endophilin binding proteins. The phase transition can be triggered by specific multivalent binding partners of endophilin in the FEME pathway such as the third intracellular loop (TIL) of the β1-AR, and the C-terminal domain of lamellipodin (LPD). Other endocytic accessory proteins can either partition into, or target interfacial regions of, these condensate droplets, and LPD also phase separates with the actin polymerase VASP. On the membrane, TIL promotes protein clustering in the presence of endophilin and LPD C-terminal domain. Our results demonstrate how the multivalent interactions between endophilin, LPD, and TIL regulate protein assembly formation on the membrane, providing mechanistic insights into the priming and initiation steps of FEME.

Date: 2022
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DOI: 10.1038/s41467-022-32529-0

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