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CCR7 signalling and ligand bias: A comprehensive characterisation using label-based and label-free methodologies KU Leuven

G protein-coupled receptors (GPCR) are intricate transmembrane proteins that relay signals from the extracellular to the intracellular environment using heterotrimeric G proteins. GPCRs mediate a vast array of physiological functions, but when deregulated, they also contribute to many pathological diseases such as diabetes, Alzheimer's disease, and cancer. This makes GPCRs an attractive therapeutic target. Indeed, approximately 35% of all Food ...

Radiosynthesis and preclinical evaluation of a 68Ga-labeled tetrahydroisoquinoline-based ligand for PET imaging of C-X-C chemokine receptor type 4 in an animal model of glioblastoma KU Leuven

Dominique Schols
BACKGROUND: This study aimed to develop a novel positron emission tomography (PET) tracer, [68Ga]Ga-TD-01, for CXCR4 imaging. To achieve this goal, the molecular scaffold of TIQ15 was tuned by conjugation with the DOTA chelator to make it suitable for 68Ga radiolabeling. METHODS: A bifunctional chelator was prepared by conjugating the amine group of TIQ15 with p-NCS-Bz-DOTA, yielding TD-01, with a high yield (68.92%). TD-01 was then radiolabeled ...

Recent advances in canonical versus non-canonical Ca2+-signaling-related anti-apoptotic Bcl-2 functions and prospects for cancer treatment KU Leuven

Geert Bultynck
Cell fate is tightly controlled by a continuous balance between cell survival and cell death inducing mechanisms. B-cell lymphoma 2 (Bcl-2)-family members, composed of effectors and regulators, not only control apoptosis at the level of the mitochondria but also by impacting the intracellular Ca2+ homeostasis and dynamics. On the one hand, anti-apoptotic protein Bcl-2, prevents mitochondrial outer membrane permeabilization (MOMP) by scaffolding ...

Structural and functional insights into transcription activation of the essential LysR-type transcriptional regulators KU Leuven

Kalyan Das
The enormous LysR-type transcriptional regulators (LTTRs), which are diversely distributed amongst prokaryotes, play crucial roles in transcription regulation of genes involved in basic metabolic pathways, virulence and stress resistance. However, the precise transcription activation mechanism of these genes by LTTRs remains to be explored. Here, we determine the cryo-EM structure of a LTTR-dependent transcription activation complex comprising ...

Development and application of NanoBRET-based technology: Unravelling signalling bias at the human chemokine receptors CXCR1 and CXCR2 KU Leuven

Katrijn Boon
G protein-coupled receptors (GPCRs) are cell surface receptors that translate extracellular stimuli into intracellular responses. They play a pivotal role in regulating developmental and physiological processes. Hence, dysregulated GPCR signalling contributes to various human pathologies, making GPCRs prime targets for FDA-approved drugs1-4. Ligand binding induces conformational changes in GPCRs, initiating both G protein-dependent signalling ...

Insights in inulin binding and inulin oligosaccharide formation by novel multi domain endo-inulinases from Botrytis cinerea KU Leuven

Arnout Voet, Wim Van den Ende
World-wide, pathogenic fungi such as Botrytis cinerea cause tremendous yield losses in terms of food production and post-harvest food decay. Many fungi produce inulin-type oligosaccharides (IOSs) from inulin through endo-inulinases which typically show a two domain structure. B.cinerea lacks a two domain endo-inulinase but contains a three domain structure instead. Genome mining revealed three and four domain (d4) enzymes in the fungal kingdom. ...

Noncanonical and reversible cysteine ubiquitination prevents the overubiquitination of PEX5 at the peroxisomal membrane. KU Leuven

Marc Fransen
PEX5, the peroxisomal protein shuttling receptor, binds newly synthesized proteins in the cytosol and transports them to the organelle. During its stay at the peroxisomal protein translocon, PEX5 is monoubiquitinated at its cysteine 11 residue, a mandatory modification for its subsequent ATP-dependent extraction back into the cytosol. The reason why a cysteine and not a lysine residue is the ubiquitin acceptor is unknown. Using an established ...

Repurposing the mammalian RNA-binding protein Musashi-1 as an allosteric translation repressor in bacteria Vrije Universiteit Brussel

Roswitha Dolcemascolo, María Heras-Hernández, Lucas Goiriz, Roser Montagud-Martínez, Alejandro Requena-Menéndez, Raúl Ruiz, Anna Pérez-Ràfols, R Anahí Higuera-Rodríguez, Guillermo Pérez Ropero, Wim Vranken, et al.

The RNA recognition motif (RRM) is the most common RNA-binding protein domain identified in nature. However, RRM-containing proteins are only prevalent in eukaryotic phyla, in which they play central regulatory roles. Here, we engineered an orthogonal post-transcriptional control system of gene expression in the bacterium Escherichia coli with the mammalian RNA-binding protein Musashi-1, which is a stem cell marker with neurodevelopmental ...

Leucine Motifs Stabilize Residual Helical Structure in Disordered Proteins Vrije Universiteit Brussel

Uroš Zavrtanik, Tadej Medved, Samo Purič, Wim Vranken, Jurij Lah, San Hadži

Many examples are known of regions of intrinsically disordered proteins that fold into α-helices upon binding to their targets. These helical binding motifs (HBMs) can be partially helical also in the unbound state, and this so-called residual structure can affect binding affinity and kinetics. To investigate the underlying mechanisms governing the formation of residual helical structure, we assembled a dataset of experimental helix contents ...

Cellular effects of BAPTA: Are they only about Ca2+chelation? KU Leuven

Flore Sneyers, Steven Verhelst, Geert Bultynck
Intracellular Ca2+ signals play a vital role in a broad range of cell biological and physiological processes in all eukaryotic cell types. Dysregulation of Ca2+ signaling has been implicated in numerous human diseases. Over the past four decades, the understanding of how cells use Ca2+ as a messenger has flourished, largely because of the development of reporters that enable visualization of Ca2+ signals in different cellular compartments, and ...