Functional divergence caused by mutations in an energetic hotspot in ERK2.

TitleFunctional divergence caused by mutations in an energetic hotspot in ERK2.
Publication TypeJournal Article
Year of Publication2019
AuthorsTaylor, CA, Cormier, KW, Keenan, SE, Earnest, S, Stippec, S, Wichaidit, C, Juang, Y-C, Wang, J, Shvartsman, SY, Goldsmith, EJ, Cobb, MH
JournalProc Natl Acad Sci U S A
Date Published2019 Jul 30
KeywordsAnimals, Animals, Genetically Modified, Crystallography, X-Ray, Drosophila melanogaster, Drosophila Proteins, Enzyme Activation, Enzyme Stability, Extracellular Signal-Regulated MAP Kinases, Humans, Models, Molecular, Mutant Proteins, Mutation

<p>The most frequent extracellular signal-regulated kinase 2 (ERK2) mutation occurring in cancers is E322K (E-K). ERK2 E-K reverses a buried charge in the ERK2 common docking (CD) site, a region that binds activators, inhibitors, and substrates. Little is known about the cellular consequences associated with this mutation, other than apparent increases in tumor resistance to pathway inhibitors. ERK2 E-K, like the mutation of the preceding aspartate (ERK2 D321N [D-N]) known as the sevenmaker mutation, causes increased activity in cells and evades inactivation by dual-specificity phosphatases. As opposed to findings in cancer cells, in developmental assays in , only ERK2 D-N displays a significant gain of function, revealing mutation-specific phenotypes. The crystal structure of ERK2 D-N is indistinguishable from that of wild-type protein, yet this mutant displays increased thermal stability. In contrast, the crystal structure of ERK2 E-K reveals profound structural changes, including disorder in the CD site and exposure of the activation loop phosphorylation sites, which likely account for the decreased thermal stability of the protein. These contiguous mutations in the CD site of ERK2 are both required for docking interactions but lead to unpredictably different functional outcomes. Our results suggest that the CD site is in an energetically strained configuration, and this helps drive conformational changes at distal sites on ERK2 during docking interactions.</p>

Alternate JournalProc Natl Acad Sci U S A
PubMed ID31296562
PubMed Central IDPMC6681740
Grant ListP30 CA142543 / CA / NCI NIH HHS / United States
R01 GM086537 / GM / NIGMS NIH HHS / United States
R37 DK034128 / DK / NIDDK NIH HHS / United States