Arf GTPase activates the WAVE Regulatory Complex through a novel binding site

Yang, S.; Liu, Y.; Brown, A.; Schaks, M.; Ding, B.; Kramer, D. A.; Ding, L.; Alekhina, O.; Billadeau, D. D.; Chowdhury, S.; Wang, J.; Rottner, K.; Chen, B.

doi:10.1101/2022.05.13.491857

bioRxiv · 10.1101/2022.05.13.491857

Arf GTPase activates the WAVE Regulatory Complex through a novel binding site

Yang, S.·Liu, Y.·Brown, A.·Schaks, M.·Ding, B.·Kramer, D. A.·Ding, L.·Alekhina, O.·Billadeau, D. D.·Chowdhury, S.·Wang, J.·Rottner, K.·Chen, B.

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Abstract

Crosstalk between Rho- and Arf-family GTPases plays an important role in linking actin cytoskeletal remodeling to membrane protrusion, organelle structure, and vesicle trafficking. The central actin regulator, WAVE Regulatory Complex (WRC), is a converging point of Rac1 (a Rho-family GTPase) and Arf signaling in many processes, but how Arf promotes WRC activation is unknown. Here we reconstituted a direct interaction between Arf and WRC. This interaction can be greatly enhanced by Rac1 binding to the D site of the WRC. Arf1 binds to a newly identified conserved surface on Sra1 located between the D site and the WH2 helix of WAVE1, which can drive WRC activation using a mechanism distinct from that of Rac1. Mutating Arf binding site abolishes Arf1-WRC interaction, disrupts Arf1-mediated WRC activation, and impairs lamellipodia morphology. This work uncovers a new mechanism underlying WRC activation and provides a mechanistic foundation for studying how WRC-mediated actin polymerization links Arf and Rac signaling in the cell.

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Yang, S., Liu, Y., Brown, A., Schaks, M., Ding, B., Kramer, D. A., Ding, L., Alekhina, O., Billadeau, D. D., Chowdhury, S., Wang, J., Rottner, K., Chen, B.. 2022-05-13. Arf GTPase activates the WAVE Regulatory Complex through a novel binding site. https://doi.org/10.1101/2022.05.13.491857

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