Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites

Proceedings of the National Academy of Sciences of the United States of America
Aaron J CantorJohn Kuriyan

Abstract

Upon activation, the epidermal growth factor receptor (EGFR) phosphorylates tyrosine residues in its cytoplasmic tail, which triggers the binding of Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains and initiates downstream signaling. The sequences flanking the tyrosine residues (referred to as "phosphosites") must be compatible with phosphorylation by the EGFR kinase domain and the recruitment of adapter proteins, while minimizing phosphorylation that would reduce the fidelity of signal transmission. To understand how phosphosite sequences encode these functions within a small set of residues, we carried out high-throughput mutational analysis of three phosphosite sequences in the EGFR tail. We used bacterial surface display of peptides coupled with deep sequencing to monitor phosphorylation efficiency and the binding of the SH2 and PTB domains of the adapter proteins Grb2 and Shc1, respectively. We found that the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR. Although efficient phosphorylation by EGFR can occur with either acidic or large hydrophobic residues at the -1 position with respect to the tyrosine, hydrophobi...Continue Reading

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Citations

Oct 11, 2019·Protein Science : a Publication of the Protein Society·Jordan ValgardsonJeanine F Amacher
Sep 11, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mengling YouDan Ji
Jan 2, 2019·Nature Structural & Molecular Biology·Neel H Shah, John Kuriyan
Oct 23, 2020·International Journal of Cancer. Journal International Du Cancer·Zihang LingXiaoan Tao
Aug 10, 2021·Frontiers in Oncology·Weili MinYang Zhao
Jun 11, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Rajat BanerjeeNisha J D'Silva
Oct 29, 2021·Biotechnology and Bioengineering·Makiko HorikawaMasahiro Kawahara

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Methods Mentioned

BETA
FACS
flow cytometry

Software Mentioned

NAMD
pLogo
CHARMM36

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