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

ABSTRACT: 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 stren

SUBMITTER: Polyansky AA 

PROVIDER: S-EPMC10192832 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature