Biology subjects

Larabi, A.

Publications and source records attributed to Larabi, A..

4 recordsLinked to original sources

bioRxiv2025

Key determinants of T cell epitope recognition revealed by TCR specificity profiles

Interactions between T-Cell Receptors (TCRs) and antigenic peptides presented on Major Histocompatibility Complex (MHC) molecules are central to the immune recognition of infected and malignant cells. The complexity of the TCR sequence space, the flexibility of the TCR-epitope interface and the lack of a standardized framework to visualize TCR specificity have hindered a comprehensive understanding of the principles governing TCR-epitope recognition across a broad range of epitopes. Here, we introduce a fully interpretable probabilistic framework, termed TCR specificity profiles (TSPs), which captures fundamental properties distinguishing epitope-specific from baseline TCR repertoires. We demonstrate that TSPs unravel key determinants of TCR-epitope recognition specificity. By identifying and analyzing TCRs recognizing dozens of epitope variants, we show that TSPs accurately predict cross-reactivity and reveal how TCR specificity evolves with epitope sequence, binding mode and MHC restriction. TSPs further enable interpretation of machine learning tools and reveal how AlphaFold3 can be used to decipher key determinants of TCR-epitope recognition specificity.

immunology↗

bioRxiv2025

Molecular characterization of an adhesion GPCR signal transduction

Key cellular processes rely on the transduction of extracellular mechanical signals by specialized membrane receptors, including adhesion G-protein-coupled receptors (aGPCRs). While recent studies support aGPCR activation via shedding of the extracellular GAIN domain, shedding-independent signaling mechanisms have also been observed. However, the molecular basis underlying these distinct activation modes remains poorly understood. Here, we integrate single-molecule force spectroscopy, molecular dynamics simulations, and cell-based assays to elucidate the structural and dynamic mechanisms of ADGRG1 mechanotransduction. We show that shear stress induces distinct deformation pathways in the isolated GAIN domain, promoting tethered agonist (TA) exposure through loop rearrangements prior to domain shedding. In the full-length receptor, defined GAIN orientations and specific loop contacts with the 7-transmembrane (7TM) core enable allosteric TA engagement and signaling in the absence of GAIN dissociation. The directionality of the applied force dictates the activation pathway, favoring either GAIN shedding or intact GAIN-7TM coupling. These mechanisms align with both the basal activity and collagen-enhanced signaling of ADGRG1. Using deep learning-guided design, we engineered GAIN variants with tailored mechanical sensitivity, validating our model through predictable shifts in constitutive and ligand-induced signaling. Together, our findings establish a unified framework for aGPCR activation governed by GAIN dynamics and orientation, bridging mechanical and allosteric models of receptor function and providing new strategies for engineering mechanosensitive receptors and precision therapeutics.

biophysics↗

bioRxiv2023

Uncovering and engineering the mechanical properties of the adhesion GPCR ADGRG1 GAIN domain

Key cellular functions depend on the transduction of extracellular mechanical signals by specialized membrane receptors including adhesion G-protein coupled receptors (aGPCRs). While recently solved structures support aGPCR activation through shedding of the extracellular GAIN domain, the molecular mechanisms underpinning receptor mechanosensing remain poorly understood. When probed using single-molecule atomic force spectroscopy and molecular simulations, ADGRG1 GAIN dissociated from its tethered agonist at forces significantly higher than other reported signaling mechanoreceptors. Strong mechanical resistance was achieved through specific structural deformations and force propagation pathways under mechanical load. ADGRG1 GAIN variants computationally designed to lock the alpha and beta subdomains and rewire mechanically-induced structural deformations were found to modulate the GPS-Stachel rupture forces. Our study provides unprecedented insights into the molecular underpinnings of GAIN mechanical stability and paves the way for engineering mechanosensors, better understanding aGPCR function, and informing drug-discovery efforts targeting this important receptor class.

biophysics↗

bioRxiv2022

Machine learning predictions of MHC-II specificities reveal alternative binding mode of class II epitopes

CD4+ T cells orchestrate the adaptive immune response against pathogens and cancer by recognizing epitopes presented on MHC-II molecules. The high polymorphism of MHC-II genes represents an important hurdle towards accurate prediction and identification of CD4+ T-cell epitopes in different individuals and different species. Here we collected and curated a dataset of 627,013 unique MHC-II ligands identified by mass spectrometry. This enabled us to precisely determine the binding motifs of 88 MHC-II alleles across human, mouse, cattle and chicken. Analysis of these binding specificities combined with X-ray crystallography refined our understanding of the molecular determinants of MHC-II motifs and revealed a widespread reverse binding mode in MHC-II ligands. We then developed a machine learning framework to accurately predict binding specificities and ligands of any MHC-II allele. This tool improves and expands predictions of CD4+ T-cell epitopes, and enabled us to discover and characterize several viral and bacterial epitopes following the aforementioned reverse binding mode.

immunology↗