Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/27701 |
| _version_ | 1811236856451301376 |
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| author | Li He Helena Steinocher Ashish Shelar Emily B Cohen Erin N Heim Birthe B Kragelund Gevorg Grigoryan Daniel DiMaio |
| author_facet | Li He Helena Steinocher Ashish Shelar Emily B Cohen Erin N Heim Birthe B Kragelund Gevorg Grigoryan Daniel DiMaio |
| author_sort | Li He |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:16:21Z |
| format | Article |
| id | doaj.art-0c943039475e4f7da16907be3642d2a5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:16:21Z |
| publishDate | 2017-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0c943039475e4f7da16907be3642d2a52022-12-22T03:33:25ZengeLife Sciences Publications LtdeLife2050-084X2017-09-01610.7554/eLife.27701Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactionsLi He0Helena Steinocher1Ashish Shelar2Emily B Cohen3Erin N Heim4Birthe B Kragelund5https://orcid.org/0000-0002-7454-1761Gevorg Grigoryan6Daniel DiMaio7https://orcid.org/0000-0002-2060-5977Department of Genetics, Yale School of Medicine, New Haven, United StatesDepartment of Biology, Structural and NMR Laboratory, University of Copenhagen, Copenhagen, DenmarkDepartment of Genetics, Yale School of Medicine, New Haven, United StatesDepartment of Genetics, Yale School of Medicine, New Haven, United StatesDepartment of Genetics, Yale School of Medicine, New Haven, United StatesDepartment of Biology, Structural and NMR Laboratory, University of Copenhagen, Copenhagen, DenmarkDepartment of Computer Science, Dartmouth College, Hanover, United StatesDepartment of Genetics, Yale School of Medicine, New Haven, United States; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, United States; Department of Molecular Biophysics & Biochemistry, Yale School of Medicine, New Haven, United States; Yale Cancer Center, New Haven, United StatesTransmembrane 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.https://elifesciences.org/articles/27701transmembrane proteinsprotein-protein interacctionstraptamersmembraneNMRmolecular dynamics |
| spellingShingle | Li He Helena Steinocher Ashish Shelar Emily B Cohen Erin N Heim Birthe B Kragelund Gevorg Grigoryan Daniel DiMaio Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions eLife transmembrane proteins protein-protein interacctions traptamers membrane NMR molecular dynamics |
| title | Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions |
| title_full | Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions |
| title_fullStr | Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions |
| title_full_unstemmed | Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions |
| title_short | Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions |
| title_sort | single methyl groups can act as toggle switches to specify transmembrane protein protein interactions |
| topic | transmembrane proteins protein-protein interacctions traptamers membrane NMR molecular dynamics |
| url | https://elifesciences.org/articles/27701 |
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