Dynamin 1xA Interaction with Endophilin A1 for Ultrafast Endocytosis

Core Concepts

The long tail variant of Dynamin 1xA interacts with Endophilin A1 through a newly identified binding site, regulating ultrafast endocytosis at synapses.

Abstract

Dynamin 1 (Dyn1) has two splice variants, xA and xB, with unique C-terminal extensions. Dyn1xA accelerates vesicle fission during ultrafast endocytosis by binding to Endophilin A. The interaction is regulated by phosphorylation and determines specificity for ultrafast endocytosis. Mutations disrupting the interaction cause mislocalization of Dyn1xA along axons and stalled endocytic pits on the plasma membrane. The study reveals a novel binding site for Endophilin A in the long tail extension of Dyn1xA, essential for ultrafast endocytosis at synapses.

Stats

Dynamin 1xA accelerates vesicle fission during ultrafast endocytosis. Mutations disrupting the interaction cause mislocalization of Dyn1xA along axons. The study reveals a novel binding site for Endophilin A in the long tail extension of Dyn1xA.

Quotes

"The specificity for ultrafast endocytosis is defined by the phospho-regulated interaction of Endophilin A through a newly identified site of Dyn1xA’s long tail." "Endophilin A binds to a specific PRM near phosphobox-2 with higher affinity than its previously known site."

Key Insights Distilled From

Dynamin 1xA interacts with Endophilin A1 via its spliced long C-terminus for ultrafast endocytosis

by Imoto,Y., Xu... at www.biorxiv.org 09-21-2023

https://www.biorxiv.org/content/10.1101/2023.09.21.558797v2

Deeper Inquiries

How does the phosphorylation state of Dynamin affect its interactions with other proteins

The phosphorylation state of Dynamin plays a crucial role in regulating its interactions with other proteins. In the context provided, Dynamin 1 has two major splice variants, xA and xB, each containing unique C-terminal extensions. These extensions contain specific phosphorylation sites that modulate the binding affinity of Dynamin for different endocytic proteins. For example, phosphobox-1 contains serine residues S774 and S778, which regulate interactions with Syndapin 1. On the other hand, phosphobox-2 includes serine residues S851 and S857 that impact interactions with Endophilin A. Phosphorylation at these sites acts as a switch to control protein-protein interactions involving Dynamin. When these serine residues are dephosphorylated or mutated to mimic a phosphorylated state (phosphomimetic mutants), it alters the binding affinities of Dynamin for specific partners like Endophilin A or Amphiphysin 1. This dynamic regulation allows for precise control over endocytic processes by fine-tuning protein interactions based on cellular signaling cues.

What implications do these findings have for understanding synaptic function and dysfunction

The findings regarding how Dynamin interacts with Endophilin A through its spliced long C-terminus have significant implications for understanding synaptic function and dysfunction. At synapses, ultrafast endocytosis is critical for rapid retrieval of synaptic vesicle membranes during neurotransmission events. The localization and function of specific splice variants like Dyn1xA play a key role in this process. Understanding how the long tail extension of Dyn1xA interacts preferentially with Endophilin A sheds light on the molecular mechanisms underlying ultrafast endocytosis at synapses. Disruptions in these protein-protein interactions due to mutations or altered phosphorylation states can lead to defects in endocytic pathways, impacting synaptic vesicle recycling and neurotransmitter release efficiency. These insights provide valuable information about the molecular basis of synaptic transmission and could help elucidate potential mechanisms underlying neurological disorders associated with dysfunctional endocytosis processes at synapses.

How might disruptions in protein interactions impact therapeutic strategies targeting endocytic pathways

Disruptions in protein interactions involved in endocytic pathways can have profound effects on cellular functions and may contribute to various disease conditions. In the context described above, alterations in the interaction between Dynamin 1xA's long tail extension and Endophilin A could impact ultrafast endocytosis at synapses. Therapeutic strategies targeting endocytic pathways rely on understanding these intricate protein-protein interactions to develop interventions that restore normal cellular function. If disruptions occur due to mutations affecting binding interfaces or changes in phosphorylation status regulating these interactions, therapeutic approaches must consider restoring proper protein associations. For instance, drugs designed to modulate kinase activity responsible for phosphorylating key residues on dynamin could potentially regulate its interaction with partner proteins like Endophilin A more effectively during synaptic vesicle recycling processes.