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Elife. 2017 Sep 4;6. pii: e27701. doi: 10.7554/eLife.27701.

Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions.

Author information

1
Department of Genetics, Yale School of Medicine, New Haven, United States.
2
Department of Biology, Structural and NMR Laboratory, University of Copenhagen, Copenhagen, Denmark.
3
Department of Computer Science, Dartmouth College, Hanover, United States.
4
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, United States.
5
Department of Molecular Biophysics & Biochemistry, Yale School of Medicine, New Haven, United States.
6
Yale Cancer Center, New Haven, 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.

KEYWORDS:

NMR; biochemistry; biophysics; membrane; molecular dynamics; none; protein-protein interacctions; structural biology; transmembrane proteins; traptamers

PMID:
28869036
PMCID:
PMC5597333
DOI:
10.7554/eLife.27701
[Indexed for MEDLINE]
Free PMC Article

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