Function of SYDE C2-RhoGAP family as signaling hubs for neuronal development deduced by computational analysis

Zen Kouchi,Masaki Kojima

doi:10.1038/s41598-022-08147-7

Abstract

Recent investigations of neurological developmental disorders have revealed the Rho-family modulators such as Syde and its interactors as the candidate genes. Although the mammalian Syde proteins are reported to possess GTPase-accelerating activity for RhoA-family proteins, diverse species-specific substrate selectivities and binding partners have been described, presumably based on their evolutionary variance in the molecular organization. A comprehensive in silico analysis of Syde family proteins was performed to elucidate their molecular functions and neurodevelopmental networks. Predicted structural modeling of the RhoGAP domain may account for the molecular constraints to substrate specificity among Rho-family proteins. Deducing conserved binding motifs can extend the Syde interaction network and highlight diverse but Syde isoform-specific signaling pathways in neuronal homeostasis, differentiation, and synaptic plasticity from novel aspects of post-translational modification and proteolysis.

Highlights

Domain might cause its degradation, and dysregulation of axonal guidance[11]; the neuronal function of mammalian Syde[2] is unknown
Syde[1] regulates synaptic exocytosis and its RhoGAP activity is a prerequisite for dendritogenesis
It was reported that the C2 domain of Syde[1] in addition to the N-terminal disordered domain has an autoinhibitory role for RhoGAP activity[3]; the current study may provide the vertebrate-specific Rho-family substrate recognition by the Syde[1] RhoGAP domain

Summary

Introduction

Domain might cause its degradation, and dysregulation of axonal guidance[11]; the neuronal function of mammalian Syde[2] is unknown. Pleckstrin homology domain-containing family G member 3 (PLEKHG3) possesses a guanidine nucleotide exchange activity and was identified as a Syde[2] complex by high-throughput immunoaffinity screening[12]. Syde-family proteins are characterized by the presence of RhoGAP and C2 motif in domain organization. Promiscuity of substrate specificity and the complex regulation of RhoGAP family proteins have been implicated in several studies using cell-based expression s ystems[6,12,15]. The structure–function relationship of the SYDE-family proteins was elucidated by in silico modeling of structural domain by combining sequence and phylogeny. The regulatory regions of the Syde proteins were identified based on the conserved candidate short linear motifs (SLiMs) located in the disordered domains of soluble proteins. Predicted interactors highlight the mammalian Syde network involved in neuronal homeostasis, with post-translational modification and RhoGAP selectivity as synaptic scaffold molecules. The hypothesis of Syde function as a neuronal signaling hub will be worth investigating experimentally and clinically in the future

Methods

Results

Conclusion