A Structural Network Analysis of Neuronal ArhGAP21/23 Interactors by Computational Modeling

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• RhoGTPase-activating proteins (RhoGAPs) are crucial for neuronal development, but their substrate specificity is not fully understood.
• ArhGAP21 and ArhGAP23 are RhoGAPs with distinct N-terminal domains (PDZ and pleckstrin homology) that influence their function.

Purpose of the Study:

• To computationally elucidate the substrate recognition mechanisms of ArhGAP21 and ArhGAP23.
• To analyze the structural basis for RhoGTPase interaction and the functional roles of their domains.
• To investigate the signaling pathways regulated by ArhGAP21/23 in mammalian systems.

Main Methods:

• Computational modeling using template-based methods and AlphaFold2.
• Protein docking simulations with HADDOCK and HDOCK to predict RhoGTPase interactions.
• Peptide docking analysis to identify specific domain-ligand interactions.
• In silico analysis of domain structures and functional selectivity.

Main Results:

• ArhGAP21 predicted to target Cdc42, RhoA, RhoB, RhoC, RhoG, and downregulate RhoD/Tc10.
• ArhGAP23 predicted to target RhoA and Cdc42, with less efficient RhoD downregulation.
• PDZ domains of ArhGAP21/23 share conserved structural features with MAST-family proteins.
• ArhGAP23 PDZ domain specifically interacts with the PTEN C-terminus.
• Identification of mammalian-specific Arf- and RhoGTPase-regulated signaling pathways.

Conclusions:

• ArhGAP21 and ArhGAP23 exhibit distinct RhoGTPase substrate specificities, contributing to their diverse roles.
• Domain structures and interactions, including PDZ-PTEN binding, underpin RhoGAP functionality.
• ArhGAP21/23-specific signaling pathways are essential for synaptic homeostasis and axonal/dendritic transport.