Biology subjects

Enkavi, G.

Publications and source records attributed to Enkavi, G..

3 recordsLinked to original sources

bioRxiv2026

Structural Rewiring of IL-7R Dimerization by an Oncogenic Transmembrane Mutation Can Be Reversed by Rational Design

Mutations within the transmembrane domains (TMDs) of single-pass transmembrane receptors often cause aberrant, ligand-independent receptor signaling associated with diverse malignancies, but their mechanism of action remain largely unknown. These TMD mutations are generally not targetable as they are buried in membrane. Here, we determined the mechanism of a gain-of-function (GOF) TMD mutation of interleukin-7 receptor (IL-7R) associated with T-cell acute lymphoblastic leukemia, and addressed the possibility of directly targeting the TMD mutation by using rationally designed transmembrane helices to restore order to uncontrolled signaling. We find that the GOF mutation of IL-7R severely shifts the TMD homodimerization interface, causing the receptor to homodimerize in a geometry that activates downstream signaling independent of ligand. Designed transmembrane helices that interfere with the new interface, delivered with mRNA technology, selectively block ligand-independent but not ligand-dependent signaling. Our study provides a conceptual framework for understanding and repairing disease-causing TMD mutations of single-pass cytokine receptors.

biophysics↗

bioRxiv2025

Adhesion-derived condensates control component availability to regulate adhesion dynamics

Integrin adhesion complexes mediate cell-extracellular matrix (ECM) interactions and undergo dynamic remodelling to regulate cell adhesion and migration. Here, we demonstrate that tensin 1 (TNS1), a multidomain adhesion adaptor protein linking active integrins with the actin cytoskeleton, undergoes phase separation in cells. Endogenous TNS1 condensates are formed upon focal adhesion disassembly or limited integrin-ECM engagement in both 2D and 3D environments, acting as reservoirs for inactive adhesion proteins. Combining functional experimental approaches with phosphoproteomics, we identify the TNS1 intrinsically disordered region as the main driver of TNS1 condensation and demonstrate a negative regulatory role of phosphorylation on condensate assembly upon activation of stress-responsive kinases. Finally, we confirm the functional effects of phosphorylation-dependent TNS1 condensation on adhesion dynamics and cell migration. Together, our findings highlight TNS1 condensation as a regulatory mechanism controlling local availability of inactive adhesion proteins, with direct implications on adhesion dynamics and cell behaviour.

cell biology↗

bioRxiv2019

Antidepressants act by binding to the cholesterol-interaction site at TRKB neurotrophin receptor

It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of TRKB, the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and the allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which proposes a framework for how molecular effects of antidepressants are translated into clinical mood recovery.

neuroscience↗