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

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.

SUBMITTER: Karl K

PROVIDER: S-EPMC8649073 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Karl Kelly K Hristova Kalina K

Current opinion in structural biology 20210813

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 extracellu ...[more]

PMID: 34399300

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Project description:The ability to sense and respond to environmental cues is essential for adaptation and survival in living organisms. In bacteria, this process is accomplished by multidomain sensor histidine kinases that undergo autophosphorylation in response to specific stimuli, thereby triggering downstream signaling cascades. However, the molecular mechanism of allosteric activation is not fully understood in these important sensor proteins. Here, we report the full-length crystal structure of a blue light photoreceptor LOV histidine kinase (LOV-HK) involved in light-dependent virulence modulation in the pathogenic bacterium Brucella abortus Joint analyses of dark and light structures determined in different signaling states have shown that LOV-HK transitions from a symmetric dark structure to a highly asymmetric light state. The initial local and subtle structural signal originated in the chromophore-binding LOV domain alters the dimer asymmetry via a coiled-coil rotary switch and helical bending in the helical spine. These amplified structural changes result in enhanced conformational flexibility and large-scale rearrangements that facilitate the phosphoryl transfer reaction in the HK domain.IMPORTANCE Bacteria employ two-component systems (TCSs) to sense and respond to changes in their surroundings. At the core of the TCS signaling pathway is the multidomain sensor histidine kinase, where the enzymatic activity of its output domain is allosterically controlled by the input signal perceived by the sensor domain. Here, we examine the structures and dynamics of a naturally occurring light-sensitive histidine kinase from the pathogen Brucella abortus in both its full-length and its truncated constructs. Direct comparisons between the structures captured in different signaling states have revealed concerted protein motions in an asymmetric dimer framework in response to light. Findings of this work provide mechanistic insights into modular sensory proteins that share a similar modular architecture.

Dataset Information

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

Publications

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

Similar Datasets

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