Biology subjects

Pollmann, C.

Publications and source records attributed to Pollmann, C..

4 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↗

bioRxiv2024

Design of facilitated dissociation enables control over cytokine signaling duration

Protein design has focused primarily on the design of ground states, ensuring they are sufficiently low energy to be highly populated1. Designing the kinetics and dynamics of a system requires, in addition, the design of excited states that are traversed in transitions from one low-lying state to another2,3. This is a challenging task as such states must be sufficiently strained to be poorly populated, but not so strained that they are not populated at all, and because protein design methods have generally focused on creating near-ideal structures4-7. Here we describe a general approach for designing systems which use an induced-fit power stroke8 to generate a structurally frustrated9 and strained excited state, allosterically driving protein complex dissociation. X-ray crystallography, double electron-electron resonance spectroscopy, and kinetic binding measurements demonstrate that incorporating excited states enables design of effector-induced increases in dissociation rates as high as 6000-fold. We highlight the power of this approach by designing cytokine mimics which can be dissociated within seconds from their receptors.

biochemistry↗

bioRxiv2023

Tuning of granulopoietic signaling by de novo designed agonists

Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune the granulocyte-colony stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. Unlike G-CSF, they achieve selective activation of gene sets with hematopoietic functions with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and open up ways for new therapeutic applications for designed cytokines. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/568662v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@af56e3org.highwire.dtl.DTLVardef@171920forg.highwire.dtl.DTLVardef@12c2c0aorg.highwire.dtl.DTLVardef@ff7556_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

The adipokine Leptin activates its type I cytokine receptor (LEP-R) in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility, and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Here, we show that Leptin:LEP-R assemblies adopt an unprecedented structure within the type I cytokine receptor family featuring 3:3 stoichiometry. We validate Leptin-induced trimerization of LEP-R in the plasma membrane of living cells via multicolor single molecule microscopy. In mediating such assemblies Leptin undergoes drastic restructuring that activates its site III for binding to the Ig-domain of an adjacent LEP-R molecule in the complex. These interactions are abolished by pathological mutations linked to obesity. Collectively, our study uncovers an evolutionarily conserved Leptin:LEP-R assembly as a new mechanistic blueprint for Leptin-mediated signaling in physiology and disease, including insights into how the lowly abundant signaling-competent isoforms of LEP-R can productively participate in signaling.

molecular biology↗