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

Anton A Polyansky; Roman G Efremov

doi:10.1016/j.csbj.2023.04.021

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

Comput Struct Biotechnol J. 2023 Apr 23:21:2837-2844. doi: 10.1016/j.csbj.2023.04.021. eCollection 2023.

Authors

Anton A Polyansky¹, Roman G Efremov^{2

3

4}

Affiliations

¹ Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna BioCenter 5, A-1030 Vienna, Austria.
² Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., 117997 Moscow, Russia.
³ National Research University Higher School of Economics, 20 Myasnitskaya St., Moscow 101000, Russia.
⁴ Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow region, 141701, Russia.

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 strengthened by tight protein-protein interactions, while the wild type TM tetramer demonstrates looser packing and a tendency to dissociate. Moreover, 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 operate as mechanical hinges. This leads to dynamic decoupling of the C-termini from the rigidified N-terminal parts and facilitates more pronounced possible displacement between the C-termini of the mutant TM helical regions that can provide more freedom for mutual rearrangement of the kinase domains located downstream. Our results for the V536E mutation in the context of PDGFRA TM tetramer allow for the possibility that the effect of oncogenic TM mutations can go beyond alternating the structure and dynamics of TM dimeric states and might also promote the formation of higher-order oligomers directly contributing to ligand-independent signalling effectuated by PDGFRA and other RTKs.

Keywords: Model membranes; Molecular dynamics simulations; Pathological mutations; Protein oligomerization; Signal transduction; Structure prediction.