Structural analyses of Kek1's interaction with EGFR

Boucher, Alexander

Student Work

Structural analyses of Kek1's interaction with EGFR

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The Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that control processes such as cell survival, proliferation, differentiation, and migration. Humans have four EGFR/ErbB family members, hErbB1-4, all of which have been associated with a broad array of cancers (Burgess, et al., 2003). Previously the lab discovered an inhibitor, Kekkon1 (Kek1), of the Drosophila EGFR (dEGFR) (Ghiglione et al., 1999). Work from another group, suggested Kek1 also binds to the human receptors (Ghiglione, et al., 2003). However, more recent work suggests Kek1 does not associate with the hErbBs, which differ in that their extracellular structure consists of only four domains (I-IV), while the fly receptor has an additional fifth domain (V) (Putnam, 2021). Domain V of dEGFR is necessary for its interaction with Kek1, but modules 6&7 (m6/7) of Domain IV are also critical (Putnam, 2021). Together, these regions were sufficient in conferring Kek1 binding with hErbB2 (Putnam, 2021). One model for this requirement for dEGFR Domain IV modules 6&7, in addition to its Domain V, was a loop in hErbB2 domain IVm6, absent in the dEGFR, sterically hindered Kek1’s access to Domain V in a hErbB2+V chimera. To directly test this model, five chimera iterations of hErbB2+V with decreasing amounts of Domain IV from hErbB2, and one deleting only hErbB2’s Domain IV m6 loop, were tested for Kek1 binding. In addition, to gain further insight into the Kek1/dEGFR interaction, protein modeling software, AlphaFold2, and ChimeraX-1.5, was used to predict the binding interface between Kek1 and dEGFR.

This report represents the work of one or more WPI undergraduate students submitted to the faculty as evidence of completion of a degree requirement. WPI routinely publishes these reports on its website without editorial or peer review.

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