The transmembrane domain (TMD) of single pass membrane receptors is actively contributing to receptor dimerization. It is therefore a crucial component of cell signaling by modulating the nature and the stability of TMD/TMD interactions in response to ligand binding. We have shown that the TMD of Neuropilin-1 (NRP1) exhibits a double GxxxGxxxG motive required to trigger migratory and proliferative behaviors in different cell types (Roth et al., 2008 Mol. Biol. Cell.; Nasarre et al., 2010 Oncogene; Arpel et al., 2016 Oncotarget). The biological functions of TMD have also been demonstrated for other cancer-associated receptors such as HER2 (Arpel et al., 2014 Cell Reports) or Plexin-A1 (Jacob et al., 2016 Oncotarget). From this extensive biological work we performed coarse grain simulations to analyze and predict the nature of the amino acids necessary and/or sufficient to establish robust TMD interfaces (Aci-Sèche et al., 2014 PlosOne). Bacterial two-hybrid systems were also used to demonstrate the large but specific spectrum of TMD interactions (Sawma et al., 2014 Biol. Mol. Cell). This accumulation of evidence supporting the idea of a real code of interactions in TMD led us to endeavor a systematic analysis of TMD interactions for receptors with therapeutic potential. The combination of PREDDIMER and PISA approaches turn out to be an interesting tool to identify the dimerization propensity of TMD and provided sufficient information to design peptides interfering with the dimerization. Hence, we established a process enabling the production of TMD targeting synthetic peptides designed to interfere with receptor dimerization. The analysis of the biological functions of such peptides should nourish in silico approaches to develop validated structure-activity relationship methodology required to fully envision TMD as a source of novel therapeutic targets and peptides mimicking TMD as a novel class of drugs.<br/>

From the simulation of transmembrane domain of single pass receptors to therapeutic strategies

2019 Spring National Meeting

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