Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cell Biology | Enzymes and Coenzymes | Fungi | Investigative Techniques
The MAP kinase cascade is a ubiquitous eukaryotic signaling module that can be controlled by a diverse group of scaffold proteins. In budding yeast, activation of the mating MAP kinase cascade involves regulated membrane recruitment of the archetypal scaffold protein Ste5. This event promotes activation of the first kinase, but it also enhances subsequent signal propagation through the remainder of the cascade. By studying this latter effect, we find that membrane recruitment promotes signaling in trans between kinases on separate Ste5 molecules. First, trans signaling requires all Ste5 domains that mediate membrane recruitment, including both protein-binding and membrane-binding domains. Second, artificial membrane tethering of Ste5 can drive trans signaling, bypassing the need for native localization domains. Third, trans signaling can occur even if the first kinase does not bind the scaffold but instead is localized independently to the plasma membrane. Moreover, the trans signaling reaction allowed us to separate Ste5 into distinct functional domains, and then achieve normal regulation of signal output by tethering one domain to the membrane and stimulating membrane recruitment of the other. Overall, the results support a heterogeneous “ensemble” model of signaling in which scaffolds need not organize multiprotein complexes but instead can serve as binding sinks that co-concentrate enzymes and substrates at specific subcellular locales. These properties relax assembly constraints for scaffold proteins, increase regulatory flexibility, and can facilitate both natural evolution and artificial design of new signaling proteins and pathways.
MAP kinase cascade, Ste5, MAPK Pathway Signaling, proteins
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.
DOI of Published Version
bioRxiv 673855; doi: https://doi.org/10.1101/673855. Link to preprint on bioRxiv service.
Lamson RE, Winters MJ, Pryciak PM. (2019). Ste5 Membrane Localization Allows MAPK Pathway Signaling in trans Between Kinases on Separate Scaffold Molecules. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/673855. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1617
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