1 Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
2 Human Health Therapeutics Research Centre, National Research Council Canada, Montreal, QC H4P 2R2, Canada.
3 Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, H9X 3V9 QC, Canada.
4 Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada.

The adaptor protein Ste50 directly modulates yeast MAPK signaling specificity through differential connections of its RA domain.

Mol Biol Cell. 2019 03 15;30(6):794-807

Authors: Sharmeen N, Sulea T, Whiteway M, Wu C

Abstract

Discriminating among diverse environmental stimuli is critical for organisms to ensure their proper development, homeostasis, and survival. Saccharomyces cerevisiae regulates mating, osmoregulation, and filamentous growth using three different MAPK signaling pathways that share common components and therefore must ensure specificity. The adaptor protein Ste50 activates Ste11p, the MAP3K of all three modules. Its Ras association (RA) domain acts in both hyperosmolar and filamentous growth pathways, but its connection to the mating pathway is unknown. Genetically probing the domain, we found mutants that specifically disrupted mating or HOG-signaling pathways or both. Structurally these residues clustered on the RA domain, forming distinct surfaces with a propensity for protein-protein interactions. GFP fusions of wild-type (WT) and mutant Ste50p show that WT is localized to the shmoo structure and accumulates at the growing shmoo tip. The specifically pheromone response-defective mutants are severely impaired in shmoo formation and fail to localize ste50p, suggesting a failure of association and function of Ste50 mutants in the pheromone-signaling complex. Our results suggest that yeast cells can use differential protein interactions with the Ste50p RA domain to provide specificity of signaling during MAPK pathway activation.

PMID: 30650049 [PubMed - in process]