# Oligomerization-dependent and synergistic regulation of Cdc42 GTPase cycling by a GEF and a GAP

## TL;DR

The paper explains how two proteins, Cdc24 and Rga2, work together to regulate the activity of Cdc42, a key player in cell polarity, through a synergy that may be common in eukaryotic cells.

## Contribution

The study reveals a novel synergy between a GEF and a GAP in regulating Cdc42, involving mutual modulation of self-inhibition.

## Key findings

- Cdc24's GEF activity is nonlinear and depends on oligomerization.
- Rga2's GAP activity saturates at higher concentrations due to self-inhibition.
- Cdc24 and Rga2 synergistically enhance Cdc42's GTPase activity through weak binding.

## Abstract

Cell polarity is a crucial biological process essential for cell division, directed growth, and motility. In Saccharomyces cerevisiae, polarity establishment centers around the small Rho-type GTPase Cdc42, which cycles between GTP-bound and GDP-bound states, regulated by GEFs like Cdc24 and GAPs such as Rga2. To dissect the dynamic regulation of Cdc42, we employed in vitro GTPase assays, revealing inverse concentration-dependent profiles for Cdc24 and Rga2: with increasing concentration, Cdc24’s GEF activity is nonlinear and oligomerization-dependent, which is possibly linked to the relief of its self-inhibition. In contrast, Rga2’s GAP activity saturates, likely due to self-inhibition upon oligomerization. Together, Cdc24 and Rga2 exhibit a strong synergy driven by weak Cdc24–Rga2 binding. We propose that the synergy stems from Cdc24 alleviating the self-inhibition of oligomeric Rga2. We believe this synergy contributes to efficient regulation of Cdc42’s GTPase cycle over a wide range of cycling rates, enabling cells to resourcefully establish polarity. As Cdc42 is highly conserved among eukaryotes, we propose the GEF–GAP synergy to be a general regulatory property in other eukaryotes.

The GEF Cdc24 and the GAP Rga2, key regulators of the GTPase Cdc42 in Saccharomyces cerevisiae, exhibit a concentration-dependent and synergistic regulation of Cdc42 activity. The findings suggest that GEF-GAP synergy, through mutual modulation of self-inhibition, enables robust control of cell polarity - a mechanism likely conserved across eukaryotes.

Cdc24’s GEF activity is non-linear and oligomerization-dependent.Rga2’s GAP activity saturates at higher concentrations, whereas the isolated GAP domain does not.Cdc24 and Rga2 synergistically boost Cdc42’s GTPase activity through weak binding.

Cdc24’s GEF activity is non-linear and oligomerization-dependent.

Rga2’s GAP activity saturates at higher concentrations, whereas the isolated GAP domain does not.

Cdc24 and Rga2 synergistically boost Cdc42’s GTPase activity through weak binding.

The GEF Cdc24 and the GAP Rga2, key regulators of the GTPase Cdc42 in Saccharomyces cerevisiae, exhibit a concentration-dependent and synergistic regulation of Cdc42 activity.