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

TY - JOUR

T1 - Single methyl groups can act as toggle switches to specify transmembrane protein-protein interactions

AU - He, Li

AU - Steinocher, Helena

AU - Shelar, Ashish

AU - Cohen, Emily B.

AU - Heim, Erin N.

AU - Kragelund, Birthe Brandt

AU - Grigoryan, Gevorg

AU - DiMaio, Daniel

PY - 2017/9/4

Y1 - 2017/9/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029788962&partnerID=8YFLogxK

U2 - 10.7554/eLife.27701

DO - 10.7554/eLife.27701

M3 - Journal article

C2 - 28869036

AN - SCOPUS:85029788962

SN - 2050-084X

VL - 6

JO - eLife

JF - eLife

M1 - e27701

ER -