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bioRxiv · 10.1101/2022.05.13.491788

Dendrite branching receptor HPO-30 uses two novel mechanisms to regulate actin cytoskeletal remodeling

Kramer, D. A.·Narvaez-Ortiz, H. Y.·Roche, J.·Nolen, B. J.·Chen, B.
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Abstract

Dendrite morphogenesis is essential for neural circuit formation, yet the molecular mechanisms underlying complex dendrite branching remain elusive. Previous studies on the highly branched C. elegans PVD sensory neuron identified a membrane co-receptor complex that links extracellular signals to intracellular actin remodeling machinery, promoting high-order dendrite branching. In this complex, the claudin-like transmembrane protein HPO-30 recruits the WAVE regulatory complex (WRC) to dendrite branching sites, stimulating the Arp2/3 complex to polymerize actin. We report here our biochemical and structural analysis of this interaction, revealing that the intracellular domain (ICD) of HPO-30 is intrinsically disordered and employs two distinct mechanisms to regulate the actin cytoskeleton. First, HPO-30 ICD binding to the WRC requires dimerization and involves the entire ICD sequence, rather than a short linear peptide motif. This interaction enhances WRC activation by the GTPase Rac1. Second, HPO-30 ICD directly binds to the sides and barbed end of actin filaments. Binding to the barbed end requires ICD dimerization and inhibits both actin polymerization and depolymerization, resembling the actin capping protein CapZ. These dual functions provide an intriguing model of how membrane proteins can integrate distinct mechanisms to fine-tune local actin dynamics.

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Kramer, D. A., Narvaez-Ortiz, H. Y., Roche, J., Nolen, B. J., Chen, B.. 2022-05-13. Dendrite branching receptor HPO-30 uses two novel mechanisms to regulate actin cytoskeletal remodeling. https://doi.org/10.1101/2022.05.13.491788

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