Biology subjects

Reynders, M.

Publications and source records attributed to Reynders, M..

5 recordsLinked to original sources

bioRxiv2025

Logic-gating the HaloTag system with Conditional-Halo-ligator 'CHalo' reagents

HaloTag proteins spontaneously ligate onto any chemical reagent featuring a chloroalkane motif (CA). We introduce the conditional CHalo motif, which ligates to HaloTag only after uncaging by light or enzymes. (1) Photo-triggered CHalo fluorogenic reagents allow spatiotemporally-specific labeling; (2) photo-triggered CHalo heterodimerisers can photocontrol protein recruitment; and (3) enzyme-triggered CHalo reagents can durably record diverse enzyme activities, and multiplexing them should allow quantitative ratiometric recording of multiple activities in parallel. CHalo thus permits manifold extensions to the HaloTag technology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/676741v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@d18cd6org.highwire.dtl.DTLVardef@175694forg.highwire.dtl.DTLVardef@154ffd5org.highwire.dtl.DTLVardef@167fec2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Photoswitchable Molecular Glues Enable Optical Control of Transcription Factor Degradation

Immunomodulatory drugs (IMiDs), which include thalidomide and its derivatives, have emerged as the standard of care against multiple myeloma. They function as molecular glues that bind to the E3 ligase cereblon (CRBN) and induce protein interactions with neosubstrates, including the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). The subsequent ubiquitylation and degradation of these transcription factors underlies the antiproliferative activity of IMiDs. Here, we introduce photoswitchable immunomodulatory drugs (PHOIMiDs) that can be used to degrade Ikaros and Aiolos in a light-dependent fashion. Our lead compound shows minimal activity in the dark and becomes an active degrader upon irradiation with violet light. It shows high selectivity over other transcription factors, regardless of its state, and could therefore be used to control the levels of Ikaros and Aiolos with high spatiotemporal precision.

biochemistry↗

bioRxiv2023

A Photoactivated Protein Degrader for Optical Control of Synaptic Function

Hundreds of proteins determine the function of synapses, and synapses define the neuronal circuits that subserve myriad brain, cognitive, and behavioral functions. It is thus necessary to precisely manipulate specific proteins at specific sub-cellular locations and times to elucidate the roles of particular proteins and synapses in brain function. We developed PHOtochemically TArgeting Chimeras (PHOTACs) as a strategy to optically degrade specific proteins with high spatial and temporal precision. PHOTACs are small molecules that, upon wavelength-selective illumination, catalyze ubiquitylation and degradation of target proteins through endogenous proteasomes. Here we describe the design and chemical properties of a PHOTAC that targets Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII), which is abundant and crucial for baseline synaptic function of excitatory neurons. We validate the PHOTAC strategy, showing that the CaMKII-PHOTAC is effective in mouse brain tissue. Light activation of CaMKII-PHOTAC removed CaMKII from regions of the mouse hippocampus only within 25 m of the illuminated brain surface. The optically-controlled degradation decreases synaptic function within minutes of light activation, measured by the light-initiated attenuation of evoked field excitatory postsynaptic potential (fEPSP) responses to physiological stimulation. The PHOTACs methodology should be broadly applicable to other key proteins implicated in synaptic function, especially for evaluating their precise roles in the maintenance of long-term potentiation and memory within subcellular dendritic domains.

neuroscience↗

bioRxiv2022

Optical Control of Membrane Fluidity Modulates Protein Secretion

The lipid composition of cellular membranes is dynamic and undergoes remodelling affecting biophysical properties, such as membrane fluidity, which are critical to biological function. Here, we introduce an optical approach to manipulate membrane fluidity based on exogenous synthetic fatty acid with an azobenzene photoswitch, termed FAAzo4. Cells rapidly incorporate FAAzo4 into phosphatidylcholine (PC), the major phospholipid in mammalian cells, in a concentration- and cell type-dependent manner. This generates photoswitchable PC analogs (AzoPC), which are predominantly located in the endoplasmic reticulum (ER). Irradiation causes a rapid photoisomerization that increases membrane fluidity with high spatiotemporal precision. We use these PhotoCells to study the impact of membrane mechanics on protein export from the ER and demonstrate that this two-step process has distinct membrane fluidity requirements. Our approach represents an unprecedented way of manipulating membrane fluidity in cellulo and opens novel avenues to probe roles of fluidity in a wide variety of biological processes.

cell biology↗

bioRxiv2020

Evolution, geographic spreading, and demographic distribution of Enterovirus D68

BackgroundWorldwide outbreaks of enterovirus D68 (EV-D68) in 2014 and 2016 have caused serious respiratory and neurological disease. MethodsWe collected samples from several European countries during the 2018 out-break and determined 53 near full-length genome ( whole genome) sequences. These sequences were combined with 718 whole genome and 1,987 VP1-gene publicly available sequences. FindingsIn 2018, circulating strains clustered into multiple subgroups in the B3 and A2 subclades, with different phylogenetic origins. Clusters in subclade B3 emerged from strains circulating primarily in the US and Europe in 2016, though some had deeper roots linking to Asian strains, while clusters in A2 traced back to strains detected in East Asia in 2015-2016. In 2018, all sequences from the USA formed a distinct subgroup, containing only three non-US samples. Alongside the varied origins of seasonal strains, we found that diversification of these variants begins up to 18 months prior to the first diagnostic detection during a EV-D68 season. EV-D68 displays strong signs of continuous antigenic evolution and all 2018 A2 strains had novel patterns in the putative neutralizing epitopes in the BC- and DE-loops. The pattern in the BC-loop of the USA B3 subgroup had not been detected on that continent before. Patients with EV-D68 in subclade A2 were significantly older than patients with a B3 subclade virus. In contrast to other subclades, the age distribution of A2 is distinctly bimodal and was found primarily among children and in the elderly. InterpretationWe hypothesize that EV-D68s rapid evolution of surface proteins, extensive diversity, and high rate of geographic mixing could be explained by substantial reinfection of adults. FundingUniversity of Basel and Swedish Foundation for Research and Development in Medical Microbiology

microbiology↗