Atomistic mechanism of the constitutive activation of PDGFRA via its transmembrane domain

Polyansky, Anton A.; Bocharov, Eduard V.; Velghe, Amélie; Kuznetsov, Andrei; Bocharova, Olga V.; Urban, Anatoly S.; Arseniev, Alexander S.; Žagrović, Bojan; Demoulin, Jean‐Baptiste; Efremov, Roman G.

doi:10.1016/j.bbagen.2018.09.011

Cited by 10 publications

(27 citation statements)

References 55 publications

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“…It is noteworthy that the patterns of NMR signal perturbation observed for the IRtm amide groups in the micellar and bicellar environment are apparently different. This is typical for weakly interacting TM domains of RTK-related receptors [16,52,53]. Thus, the NMR data show the principal ability of the IR TM domain to dimerize / oligomerize in different modes via alternative helix packing interfaces.…”

Section: Nmr Spectroscopy Of Ir Tm Domains In Micelles Reveals Multiple Dimeric Conformationsmentioning

confidence: 74%

Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation

Kuznetsov

Zamaletdinov

Bershatsky

et al. 2020

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Section: Nmr Spectroscopy Of Ir Tm Domains In Micelles Reveals Multiple Dimeric Conformationsmentioning

confidence: 74%

Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation

Kuznetsov

Zamaletdinov

Bershatsky

et al. 2020

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The iJM region of WT tends to aggregate more than G380R, which can be related to the changes from nonactive to constitutively active dimer and the arrangement of the IC kinase domains. The separation of the TM helix C‐terminal side in the active states was suggested for the other members of RTK, such as EGFR, ErbB2, VEGFR2, and PDGFRA …”

Section: Discussionmentioning

confidence: 98%

“…The role of the TM region in the activation has been discussed generally for RTK proteins, and the TM dimer conformation has been found to be different between the active and inactive forms in various RTK proteins . For example, biochemical experiments and computational studies on epidermal growth factor receptor (EGFR) suggested the TM dimer conformational changes from the inactive C‐terminal dimer to the active N‐terminal one .…”

Section: Introductionmentioning

confidence: 99%

Role of the N‐Terminal Transmembrane Helix Contacts in the Activation of FGFR3

et al. 2019

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Fibroblast growth factor receptor 3 (FGFR3) is a member of receptor tyrosine kinases, which is involved in skeletal cell growth, differentiation, and migration. FGFR3 transduces biochemical signals from the extracellular ligand-binding domain to the intracellular kinase domain through the conformational changes of the transmembrane (TM) helix dimer. Here, we apply generalized replica exchange with solute tempering method to wild type (WT) and G380R mutant (G380R) of FGFR3. The dimer interface in G380R is different from WT and the simulation results are in good agreement with the solid-state nuclear magnetic resonance (NMR) spectroscopy. TM helices in G380R are extended more than WT, and thereby, G375 in G380R contacts near the N-termini of the TM helix dimer. Considering that both G380R and G375C show the constitutive activation, the formation of the N-terminal contacts of the TM helices can be generally important for the activation mechanism.

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“…A. Polyansky et al, 2019). While the left-handed dimers for the mutant and WT have very similar configuration, in which helices are associated via interface I of the N-terminal parts (it contains the mutated V536, LI N -dimer), the right-handed dimers are different in these two cases.…”

Section: Pdgfra Tm Domains Are Able To Form a Tetrameric Configurationmentioning

confidence: 97%

“…A. Polyansky et al, 2019). Thus, both the WT and the V536E mutant TM-tetramers were built in the described configuration (Figure 1A) and subjected to all-atom MD simulations in a POPC lipid bilayer (see below).…”

Section: Pdgfra Tm Domains Are Able To Form a Tetrameric Configurationmentioning

confidence: 99%

On a mechanistic impact of transmembrane tetramerization in pathological activation of RTKs

Polyansky¹,

Efremov

2022

Preprint

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Constitutive activation of receptor tyrosine kinases (RTKs) via different mutation has a strong impact into development of severe human disorders, including cancer. While pathological effect of such mutations can be common on the phenotypical level, mechanistic understanding of their contribution into the receptor activation depends on the exact molecular context. Mutations in transmembrane (TM) domains represent an interesting class of pathological modifications since they can directly affect a signal transduction pathway from the receptor to the kinase domains of RTKs. Here we propose a putative activation scenario of RTK, whereby TM mutations can also promote higher order oligomerization of the receptors that leads to the subsequent ligand-free activation. To illustrate this model with all-atom resolution for a previously characterized oncogenic TM mutation V536E in platelet-derived growth factor receptor alpha (PDGFRA), we use a computational modeling framework including sequence-based structure prediction and all-atom 1 μs molecular dynamics (MD) simulations in a model membrane for the predicted configuration of the PDGFRA TM tetramers. We show that in the course of MD simulations the mutant tetramer retains stable and compact configuration, which is strengthened by tight protein-protein interactions. In contrast, the wild type tetramer demonstrates looser packing and tendency to dissociate. Such a structural organization shapes the dynamics of TM helices in the oligomeric state. Specifically, the mutation affects the characteristic motions of mutated TM helical segments by introducing additional non-covalent crosslinks in the middle of the TM tetramer, which work as mechanical hinges. This leads to dynamic decoupling of the C-termini from the rigidified N-terminal parts and facilitates higher possible displacement between the C-termini of the mutant TM helical regions. This, in turn, can provide more freedom to downstream kinase domains in their mutual rearrangement. The observed structural and dynamic effects of the V536E mutations in the context of PDGFRA TM tetramer provide an interesting possibility that an effect of oncogenic TM mutations can go beyond alternating structure and dynamics of TM dimeric states and also promote formation of higher-order oligomers that may directly contribute into the ligand independent signaling of PDGFRA and other RTKs.

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Atomistic mechanism of the constitutive activation of PDGFRA via its transmembrane domain

Cited by 10 publications

References 55 publications

Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation

Dimeric states of transmembrane domains of insulin and IGF-1R receptors: Structures and possible role in activation

Role of the N‐Terminal Transmembrane Helix Contacts in the Activation of FGFR3

On a mechanistic impact of transmembrane tetramerization in pathological activation of RTKs

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