The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

Abstract

Dendrite morphogenesis is essential to neural circuit formation, but the molecular mechanisms that control the growth of complicated dendrite branches are not well understood. Prior studies using the C. elegans PVD sensory neuron identified a multi-protein signaling complex that bridges extracellular cues with intracellular actin remodeling to promote high-order dendrite branching. In this complex, the transmembrane protein HPO-30 recruits the WAVE Regulatory Complex (WRC) to dendrite branching sites, where WRC stimulates the Arp2/3 complex to polymerize actin. Here we report biochemical and structural characterization of this interaction, revealing that the intracellular domain (ICD) of HPO-30 uses two novel mechanisms to regulate the actin cytoskeleton. First, the unstructured HPO-30 ICD undergoes dimerization and folding into a three-dimensional structure in order to bind the WRC. Second, the HPO-30 ICD directly binds to actin filaments, which stabilizes actin structures by preventing both actin polymerization and depolymerization. The novel dual functions of this dendrite receptor provide an intriguing example of how membrane proteins can use different mechanisms to locally fine-tune actin dynamics.

A human DCC variant causing mirror movement disorder reveals an essential role for the Wave regulatory complex in Netrin/DCC signaling

“…This suggests that DCC may have a second sequence that can interact with the WRC in a WIRS-independent manner. Several other neuronal proteins, including HPO-30, Retrolinkin, and cannabinoid receptor CB1, were found to interact with the WRC without using a WIRS motif (Kramer et al, 2022a; Njoo et al, 2015; Xu et al, 2016; Zou et al, 2018). However, DCC shares little sequence similarity with these non-WIRS WRC-interacting proteins, suggesting that the second binding sequence on DCC may be distinct.…”