TY - JOUR
T1 - Pondering the mechanism of receptor tyrosine kinase activation
T2 - The case for ligand-specific dimer microstate ensembles
AU - Karl, Kelly
AU - Hristova, Kalina
N1 - Funding Information:
Supported by NIH GM068619 and NSF MCB1712740 .
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.sbi.2021.07.003
DO - 10.1016/j.sbi.2021.07.003
M3 - Review article
C2 - 34399300
AN - SCOPUS:85112415538
SN - 0959-440X
VL - 71
SP - 193
EP - 199
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
ER -