Marguet, D. | Search bioRxiv

bioRxiv2025

Functional Group Composition: The Blueprint for Protein Interactions

Understanding the complex landscape of protein interactions, especially those involving intrinsically disordered proteins (IDPs), is fundamental yet challenging due to their structural heterogeneity and flexibility. Traditional sequence-based homology methods frequently fall short in characterizing IDP functions and interactions. Here, we present a novel approach leveraging supervised and unsupervised machine learning techniques, focusing exclusively on the compositional features of proteins. An Edmond-Ogston-inspired mixing model can reliably predict the degree of survivin (BIRC5) binding as a function of peptide composition alone, revealing a first interesting connection with the composition diagrams of chemical thermodynamics. By representing protein sequences through their functional group compositions, we demonstrate that specific compositions robustly predict binding interactions with survivin, an important human protein in cellular regulation pathways. Experimental validation via peptide microarray confirms the predictive power of our simplified compositional model, independent of exact amino acid sequences. Extending this method across the human proteome, we identified distinct compositional signatures correlating with survivin interactions and revealed fine grained biologically meaningful functional clusters based on compositional similarity. Our findings suggest a compositional blueprint underpinning protein interactions, offering a powerful, simplified framework to decode complex biological networks.

systems biology↗

bioRxiv2022

Light-inducible T cell engagers trigger, tune and shape the activation of primary T cells

To mount appropriate responses, T cells integrate complex sequences of receptor stimuli perceived during transient interactions with antigen presenting cells. Although it has been hypothesized that the dynamics of these interactions influence the outcome of T cell activation, methodological limitations have hindered its formal demonstration. Here, we have engineered the Light-inducible T cell engager (LiTe) system, a recombinant optogenetics-based molecular tool targeting the T Cell Receptor (TCR). The LiTe system constitutes a reversible molecular switch displaying exquisite reactivity. As proof of concept, we dissect how specific temporal patterns of TCR stimulation shape T cell activation patterns. We established that CD4+ T cells respond to intermittent TCR stimulation more efficiently than their CD8+ T cells counterparts and provide evidence that distinct sequences of TCR stimulation encode different cytokine programs. Finally, we show that the LiTe system could be exploited to create light-activated bispecific T cell engagers and manipulate tumor cell killing. Overall, the LiTe system provides new opportunities to understand how T cells integrate TCR stimulations and to trigger T cell cytotoxicity with a high spatiotemporal control.

immunology↗