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A two-component protein condensate of EGFR and Grb2 regulates Ras activation at the membrane

Chun-Wei Lin, Laura M. Nocka, Brittany Stinger, Joey DeGrandchamp, Nugent Lew, Steven Alvarez, Henry Phan, Yasushi Kondo, John Kuriyan, Jay T. Groves
doi: https://doi.org/10.1101/2021.12.12.472247
Chun-Wei Lin
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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Laura M. Nocka
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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Brittany Stinger
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
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Joey DeGrandchamp
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
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Nugent Lew
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
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Steven Alvarez
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
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Henry Phan
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
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Yasushi Kondo
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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John Kuriyan
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
4The Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
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  • For correspondence: kuriyan@berkeley.edu jtgroves@lbl.gov
Jay T. Groves
1Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
5Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
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  • For correspondence: kuriyan@berkeley.edu jtgroves@lbl.gov
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ABSTRACT

We reconstitute a phosphotyrosine-mediated protein condensation phase transition of the ∼200 residue cytoplasmic tail of the epidermal growth factor receptor (EGFR) and the adaptor protein, Grb2, on a membrane surface. The phase transition depends on phosphorylation of the EGFR tail, which recruits Grb2, and the dimerization of Grb2, which provides the crosslinking element for condensation with EGFR. The Grb2 Y160 residue plays a structurally critical role in dimer formation, and phosphorylation or mutation of Y160 prevents EGFR:Grb2 condensation. By extending the reconstitution experiment to include the guanine nucleotide exchange factor, SOS, and its substrate Ras, we further find that EGFR condensation controls the ability of SOS to activate Ras. These results identify an EGFR:Grb2 protein condensation phase transition as a regulator of signal propagation from EGFR to the MAPK pathway.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 12, 2021.
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A two-component protein condensate of EGFR and Grb2 regulates Ras activation at the membrane
Chun-Wei Lin, Laura M. Nocka, Brittany Stinger, Joey DeGrandchamp, Nugent Lew, Steven Alvarez, Henry Phan, Yasushi Kondo, John Kuriyan, Jay T. Groves
bioRxiv 2021.12.12.472247; doi: https://doi.org/10.1101/2021.12.12.472247
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A two-component protein condensate of EGFR and Grb2 regulates Ras activation at the membrane
Chun-Wei Lin, Laura M. Nocka, Brittany Stinger, Joey DeGrandchamp, Nugent Lew, Steven Alvarez, Henry Phan, Yasushi Kondo, John Kuriyan, Jay T. Groves
bioRxiv 2021.12.12.472247; doi: https://doi.org/10.1101/2021.12.12.472247

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