Biology subjects

Oggier, A.

Publications and source records attributed to Oggier, A..

5 recordsLinked to original sources

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↗

bioRxiv2025

Computational design of allosteric pathways reprograms ligand-selective GPCR signaling

G-protein-coupled receptors (GPCRs) constitute the largest family of signaling receptors and drug targets. However, understanding how variations in receptor sequence, ligand chemical structure, and binding impact signaling functions remains a challenge, hindering drug discovery. Here, we developed a computational protein structure and dynamics approach to infer and design GPCR responses to multiple ligands. We created 32 dopamine D1 and D2 receptor variants with widely reprogrammed agonist-induced signal transductions. Subtle natural and designed receptor sequence variations, predicted to alter specific structural and dynamic mechanisms of ligand responses, profoundly impacted ligand potency and efficacy in agreement with our calculations. Our study provides a rational blueprint for computing the effect of sequence polymorphisms on ligand-selective protein signaling and paves the way for advancements in pharmacogenomics, drug selectivity, and the design of signaling receptors from first principles.

biochemistry↗

bioRxiv2023

Adrenal extramedullary hematopoiesis as an inducible model of the adult hematopoietic niche

Hematopoietic Stem and Progenitor Cells (HSPCs) reside in the hematopoietic niche, a structure that regulates the balance of cellular quiescence, self-renewal and commitment in a demand-adapted manner. The bone marrow (BM) hematopoietic niche is formed by several cellular players, mainly endothelial cells, osteoblasts, adipocytes, and stromal cells. While the BM niche forms a complex structure, evidence exists for simpler, albeit functional, extramedullary hematopoietic niches. However, the composition of what constitutes the simplest unit of an HSPC supportive microenvironment remains largely unknown. Here, we show that the adult adrenal gland can be transformed into a hematopoietic supportive environment. Upon splenectomy and hormonal stimulation, the adult adrenal gland can be induced to recruit and host HSPC function, including serial transplantation. Furthermore, the adrenal stroma contains a CXCL12+ population, reminiscent of BM CXCL12-Abundant Reticular (CAR) cells. Mirroring this, we found CXCL12+ cells in patient samples obtained from a local cohort of myelolipoma, a benign adrenal tumor composed of adipose and hematopoietic tissue that constitutes the most common site of extramedullary hematopoiesis specific to the adult. We present our model as a novel tool to increase our understanding of the physiology of hematopoietic support and to facilitate the development of a boneless niche model.

cell biology↗

bioRxiv2022

Computational design of ultrasensitive flexible peptide:receptor signaling complexes for enhanced chemotaxis

Engineering protein biosensors that sensitively respond to specific biomolecules by triggering precise cellular responses is a major goal of diagnostics and synthetic cell biology. Previous biosensor designs have largely relied on binding structurally well-defined molecules. In contrast, approaches that couple the sensing of flexible compounds to intended cellular responses would greatly expand potential biosensor applications. Here, to address these challenges, we develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides. To demonstrate the power of the approach, we create ultrasensitive chemotactic receptor--peptide pairs capable of eliciting potent signaling responses and strong chemotaxis in primary human T cells. Unlike traditional approaches that engineer static binding complexes, our dynamic structure design strategy optimizes contacts with multiple binding and allosteric sites accessible through dynamic conformational ensembles to achieve unprecedented signaling efficacy and potency. Our study suggests that a conformationally adaptable binding interface coupled to a robust allosteric transmission region is a key evolutionary determinant of peptidergic GPCR signaling systems. The approach lays a foundation for designing peptide-sensing receptors and signaling peptide ligands for basic and therapeutic applications.

biophysics↗

bioRxiv2022

Computational rewiring of allosteric pathways reprograms GPCR selective responses to ligands

G-protein-coupled receptors (GPCRs) are the largest class of cell surface receptors and drug targets, and respond to a wide variety of chemical stimuli to activate diverse cellular functions. Understanding and predicting how ligand binding triggers a specific signaling response is critical for drug discovery and design but remains a major challenge. Here, computational design of GPCR allosteric functions is used to uncover the mechanistic relationships between agonist ligand chemistry, receptor sequence, structure, dynamics and allosteric signaling in the dopamine D2 receptor. Designed gain of function D2 variants for dopamine displayed very divergent G-protein signaling responses to other ligand agonists that strongly correlated with ligand structural similarity. Consistent with these observations, computational analysis revealed distinct topologies of allosteric signal transduction pathways for each ligand-bound D2 pair that were perturbed differently by the designs. We leveraged these findings by rewiring ligand-specific pathways and designed receptors with highly selective ligand responses. Overall, our study suggests that distinct ligand agonists can activate a given signaling effector through specific "allosteric activator" moieties that engage partially independent signal transmission networks in GPCRs. The results provide a mechanistic framework for understanding and predicting the impact of sequence polymorphism on receptor pharmacology, informing selective drug design and rationally designing receptors with highly selective ligand responses for basic and therapeutic applications.

bioengineering↗