Single methyl groups can act as toggle switches to specify transmembrane protein-protein interactions
- Yale School of Medicine, United States
- University of Copenhagen, Denmark
- Dartmouth College, United States
Abstract
Transmembrane domains (TMDs) engage in protein-protein interactions that regulate many cellular processes, but the rules governing the specificity of these interactions are poorly understood. To discover these principles, we analyzed 26-residue model transmembrane proteins consisting exclusively of leucine and isoleucine (called LIL traptamers) that specifically activate the erythropoietin receptor (EPOR) in mouse cells to confer growth factor independence. We discovered that the placement of a single side chain methyl group at specific positions in a traptamer determined whether it associated productively with the TMD of the human EPOR, the mouse EPOR, or both receptors. Association of the traptamers with the EPOR induced EPOR oligomerization in an orientation that stimulated receptor activity. These results highlight the high intrinsic specificity of TMD interactions, demonstrate that a single methyl group can dictate specificity, and define the minimal chemical difference that can modulate the specificity of TMD interactions and the activity of transmembrane proteins.
Article and author information
Author details
Birthe B Kragelund
Funding
National Institutes of Health (R01 CA037157)
- Daniel DiMaio
Lundbeckfonden (Lundbeck Foundation)
- Birthe B Kragelund
Novo Nordisk Foundation (Novo Nordisk Foundation)
- Birthe B Kragelund
National Institutes of Health (GM113132)
- Gevorg Grigoryan
National Science Foundation (MCB151032)
- Gevorg Grigoryan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, He et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single methyl groups can act as toggle switches to specify transmembrane protein-protein interactions
eLife 6:e27701.
https://doi.org/10.7554/eLife.27701
