Biology subjects

Peterson, F. C.

Publications and source records attributed to Peterson, F. C..

3 recordsLinked to original sources

bioRxiv2026

Atypical GPCR Activation Resolved by Nanobody Engineering

Abstract/ Summary ParagraphG protein-coupled receptors (GPCRs) are the largest family of clinically targeted proteins, yet most therapeutics target a narrow subset of structurally well-behaved receptors. The atypical chemokine receptor ACKR3 defies canonical models, displaying broad ligand recognition, high basal activity, and resistance to inhibition. Using engineered nanobodies, cryo-EM, NMR, and structure-guided pharmacology, we uncover an unconventional activation mechanism in ACKR3 that challenges established paradigms of GPCR activation. We find that receptor activity is controlled by changes in extracellular pocket volume rather than conformational rearrangements in conserved microswitches, and an expanded aromatic cluster at the intracellular transducer binding pocket stabilizes the active state. These findings redefine how GPCRs can be modulated and open new strategies for targeting pharmacologically intractable receptors.

biochemistry↗

bioRxiv2025

Heparan sulfate glycosaminoglycans mediate CXCL4 (PF4) transport across the blood-brain barrier and effects on neurogenesis

CXCL4 (PF4) is a chemokine stored in platelets that has pleiotropic effects across biological settings. These effects include driving of inflammation and fibrosis as well as reversal of the effects of ageing. We have recently demonstrated that CXCL4 function is driven, independently of known chemokine receptors, through binding to glycosaminoglycan (GAG) side chains on proteoglycans within the cell surface glycocalyx. In this study, we have used intravital imaging and radioactive tracer studies, in combination with an exogenous inhibitor and a GAG-binding CXCL4 mutant, to demonstrate that CXCL4 can enter the brain parenchyma of mice by binding to proteoglycans within the cell surface of the endothelial glycocalyx of the blood-brain barrier (BBB). Furthermore, we have also demonstrated that CXCL4 directly promotes neurogenesis in vitro, which is mediated by its ability to oligomerise and bind to GAGs. These findings provide a molecular mechanism for CXCL4 uptake and function within the brain. Furthermore, these data have important implications for understanding CXCL4 during health and disease that may enable development of CXCL4-related therapeutics for inflammatory diseases and ageing.

neuroscience↗

bioRxiv2024

CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization

Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors that mobilize AML cells into the bloodstream have failed to improve patient survival, likely reflecting persistent chemokine receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the naturally occurring oligomer of CXCL12. CXCL12-LD, in contrast to wild-type or locked monomer variants, was unable to induce chemotaxis in AML cells. CXCL12-LD binding to CXCR4 decreased G protein, {beta}-arrestin, and intracellular calcium mobilization signaling pathways, and indicated the locked dimer is a partial agonist of CXCR4. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wildtype and monomeric CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in survival, proliferation, and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist can avoid pharmacodynamic tolerance and may identify new avenues to better target G protein coupled receptors.

cancer biology↗