Pondering the mechanism of receptor tyrosine kinase activation: The case for ligand-specific dimer microstate ensembles

Kelly Karl, Kalina Hristova

Research output: Contribution to journalReview articlepeer-review

Abstract

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that regulate cell growth, differentiation, motility, and metabolism. Here, we review recent advancements in RTK structure determination and in the understanding of RTK activation. We argue that further progress in the field will necessitate new ways of thinking, and we introduce the concept that RTK dimers explore ensembles of microstates, each characterized by different kinase domain dimer conformations, but the same extracellular domain dimer structure. Many microstates are phosphorylation-competent and ensure the phosphorylation of one specific tyrosine. The prevalence of each microstate correlates with its stability. A switch in ligand will lead to a switch in the extracellular domain configuration and to a subsequent switch in the ensemble of microstates. This model can explain how different ligands produce specific phosphorylation patterns, how receptor overexpression leads to enhanced signaling even in the absence of activating ligands, and why RTK kinase domain structures have remained unresolved in cryogenic electron microscopy studies.

Original languageEnglish (US)
Pages (from-to)193-199
Number of pages7
JournalCurrent Opinion in Structural Biology
Volume71
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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