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bioRxiv · 10.1101/2023.06.26.546500

The GEF Cdc24 and GAP Rga2 synergistically regulate Cdc42 GTPase cycling

Tschirpke, S.·Daalman, W. K.-G.·Laan, L.
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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, Cdc24s GEF activity is non-linear and oligomerization-dependent, which is possibly linked to the relief of its self-inhibition. In contrast, Rga2s 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 Cdc42s 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.

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Tschirpke, S., Daalman, W. K.-G., Laan, L.. 2023-06-28. The GEF Cdc24 and GAP Rga2 synergistically regulate Cdc42 GTPase cycling. https://doi.org/10.1101/2023.06.26.546500

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