biostudies-literatureUnknown21Polyansky AAConstitutive activation of receptor tyrosine kinases (RTKs) via different mutations has a strong impact on the development of severe human disorders, including cancer. Here we propose a putative activation scenario of RTKs, whereby transmembrane (TM) mutations can also promote higher-order oligomerization of the receptors that leads to the subsequent ligand-free activation. We illustrate this scenario using a computational modelling framework comprising sequence-based structure prediction and all-atom 1 µs molecular dynamics (MD) simulations in a lipid membrane for a previously characterised oncogenic TM mutation V536E in platelet-derived growth factor receptor alpha (PDGFRA). We show that in the course of MD simulations the mutant TM tetramer retains stable and compact configuration strenComputational and structural biotechnology journal2837-2844https://www.ebi.ac.uk/biostudies/studies/S-EPMC10192832biostudies-literatureOn a mechanistic impact of transmembrane tetramerization in the pathological activation of RTKs.PMC10192832Polyansky AAEfremov RGfalseOn a mechanistic impact of transmembrane tetramerization in the pathological activation of RTKs.Constitutive activation of receptor tyrosine kinases (RTKs) via different mutations has a strong impact on the development of severe human disorders, including cancer. Here we propose a putative activation scenario of RTKs, whereby transmembrane (TM) mutations can also promote higher-order oligomerization of the receptors that leads to the subsequent ligand-free activation. We illustrate this scenario using a computational modelling framework comprising sequence-based structure prediction and all-atom 1 µs molecular dynamics (MD) simulations in a lipid membrane for a previously characterised oncogenic TM mutation V536E in platelet-derived growth factor receptor alpha (PDGFRA). We show that in the course of MD simulations the mutant TM tetramer retains stable and compact configuration stren2023-01-01T00:00:00Z20232026-05-29T02:18:44.465Z2025-02-19T02:23:01.861ZS-EPMC101928323721601910.1016/j.csbj.2023.04.021