Titel
On a mechanistic impact of transmembrane tetramerization in the pathological activation of RTKs
Autor*in
Roman G. Efremov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
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.
Stichwort
Pathological mutationsStructure predictionMolecular dynamics simulationsSignal transductionProtein oligomerizationModel membranes
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Computational and Structural Biotechnology Journal
Band
21
ISSN
2001-0370
Erscheinungsdatum
2023
Seitenanfang
2837
Seitenende
2844
Publication
Elsevier BV
Erscheinungsdatum
2023
Zugänglichkeit
Rechteangabe
© 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0