# A non-canonical ARMS-GABARAP interaction modulates dendritic spine formation and synaptic development

## TL;DR

This study reveals how ARMS, a key scaffold protein in neurons, interacts with GABARAP to control spine development and protein balance, offering new insights into brain development and disease.

## Contribution

The discovery of a non-canonical ARMS-GABARAP interaction mechanism and its role in regulating dendritic spine development and ARMS localization.

## Key findings

- ARMS interacts with GABARAP via its N-terminal ankyrin repeats, distinct from canonical LIR-dependent Atg8 interactions.
- GABARAP negatively regulates ARMS-mediated dendritic spine development and maturation in neurons.
- Disrupting the ARMS-GABARAP complex alters ARMS subcellular localization and increases its accumulation in the soma.

## Abstract

ARMS (ankyrin repeat-rich membrane spanning) is a scaffold protein essential for neurotrophic signaling, synaptic development, and cytoskeletal remodeling. Despite its central role in neuronal function, how ARMS is regulated at the molecular level remains poorly understood. Here, we identify GABARAP, an Atg8-family autophagy adaptor, as a novel ARMS-binding protein that directly interacts with its N-terminal ankyrin repeats. We present the crystal structure of the ARMS-GABARAP complex, revealing an atypical interaction mode distinct from canonical LIR-dependent Atg8 interactions. Remarkably, ARMS specifically binds to the GABARAP subfamily of Atg8 proteins, setting it apart from the LC3 subfamily. Functional analysis demonstrates that GABARAP negatively regulates ARMS-mediated dendritic spine development and maturation in hippocampal neurons. Additionally, disrupting the ARMS-GABARAP complex using ankyrin-derived peptides alters ARMS subcellular localization, increasing its accumulation in the soma of neurons. Collectively, our findings uncover a novel ARMS-GABARAP interaction mechanism, establish the regulatory role of this complex in neuronal protein homeostasis, and suggest potential therapeutic strategies for targeting scaffold protein interactions in neurodevelopmental and neurodegenerative disorders.

Scaffold-protein dynamics at synapses are critical for neuronal development, yet how the localization of membrane-anchored scaffold proteins such as ARMS is regulated remains unclear. This study shows that a direct but non-canonical interaction between ARMS and GABARAP controls dendritic spine development and synaptic maturation.

ARMS uses its N-terminal ankyrin repeat to specifically interact with the GABARAP subfamily of Atg8-family adaptor, but not with LC3 proteins.The crystal structure of the ARMS‑GABARAP complex reveals a binding mode that is distinct from previously characterized autophagy-adaptor interactions.GABARAP negatively regulates ARMS-mediated dendritic spine development in neurons.Autophagy controls ARMS protein abundance through GABARAP-dependent turnover.Ankyrin-derived peptides disrupt the ARMS-GABARAP interaction and alter ARMS subcellular localization.

ARMS uses its N-terminal ankyrin repeat to specifically interact with the GABARAP subfamily of Atg8-family adaptor, but not with LC3 proteins.

The crystal structure of the ARMS‑GABARAP complex reveals a binding mode that is distinct from previously characterized autophagy-adaptor interactions.

GABARAP negatively regulates ARMS-mediated dendritic spine development in neurons.

Autophagy controls ARMS protein abundance through GABARAP-dependent turnover.

Ankyrin-derived peptides disrupt the ARMS-GABARAP interaction and alter ARMS subcellular localization.

Turnover of the neuronal scaffold protein ARMS is regulated by autophagy, but does not involve the typical binding site in Atg8-family adaptors.