Karin Mörl's research while affiliated with University of Leipzig and other places

... Recent advancements in cryo-electron microscopy (cryo-EM) have unveiled numerous GPCR-G-protein complex structures, including those associated with C-terminally amidated peptides such as cholecystokinin, orexin, and RY-amide neuropeptide Y [12][13][14] . These analyses have shed light on the intricacies of ligand-receptor interactions and their activation mechanisms. ...

... In the first set of experiments, we performed receptor titration experiments to determine the receptor-to-arrestin-ratio that ensures saturation of the luminescence donor (Nluc-arr3) by the fluorescence acceptor (receptor-eYFP) and hence, results in reproducible measurement window for ligand concentration-response curves. Accordingly, we chose to transfect 30 ng of a modified Nluc-tagged bovine arr-3 construct [71], 3900 ng receptor construct, and 70 ng of an empty pcDNA3.1 vector. After the transfection, 150,000 cells/well were re-seeded into solid white 96-well plates in technical triplicate using a phenol red-free culture medium. ...

... Peptides consisting of amino acids exhibit the great potential in creation of theranostic agents due to their broad bioactivity and robust assembling propensity [1][2][3][4][5][6][7][8]. The targeting and penetrating features of peptides endow their applications in development of peptide-drug conjugates (PDC) through connecting peptides with payloads via a biodegradable or stimuli-cleavable linker [9][10][11], which exhibit the advantages in facile synthesis and remarkable stability and thus serve as the alternatives to antibody-drug conjugates [12][13][14][15][16][17][18]. Combining these monomeric water-soluble PDCs with the vehicle function of peptide nanostructures for efficient delivery of theranostic agents [19][20][21][22][23][24][25][26][27] leads to the conception of selfassembling PDCs formed by amphiphilic drugs (Scheme 1, top) [28,29], and the significant progress has been achieved over the past decade and was exemplified as supramolecular hydrogels for cancer immunotherapy [30][31][32][33]. ...

... Cone snails represent around 1,000 species (WoRMS Editorial Board 2022), are widely distributed, and have different hunting targets (Zhao and Antunes 2022). Thus, more and more toxins ("conotoxins") were found (∼200 toxins produced per species) in Conus species (Balaji et al. 2000;Buczek et al. 2005;Akondi et al. 2014), some of which entered clinical trials that, in one case, led to the market: the synthetic analog of a conotoxin, Ziconotide, is currently commercialized as an anesthetic (Layer and McIntosh 2006;Fedosov et al. 2012;Safavi-Hemami et al. 2019;Reynaud et al. 2020;Zhao and Antunes 2022). ...

... Our results revealed that GEP44 did not promote internalization of Y2-R (Fig. 1I). This is notable given that Y2-R internalization is a critical step in receptor desensitization; this most likely results from strong allosteric effects associated with Y2-R/Gα interactions that place the cell in a refractory state and prevent further signaling 48 . Effects of GEP44 and GEP12 on islets and muscle are mediated by both GLP-1R and Y1-R. ...

... When we calculate area under the curve (AUC) scores for the markers, Rgs5 had the highest AUC, but Rgs5 was also expressed in SMCs in our data ( Figure 2A and Figure 2-figure supplement 1C). Pln, Ednra, Gpc3, and Npy1r also seemed to be candidate markers, but the literature search excluded these genes as they are also expressed in the SMCs of other tissues or different cell types Haghighi et al., 2014;Kowalczyk et al., 2015;Wittrisch et al., 2020). Atp1b2 was also excluded because its protein expression was detected in both mouse cavernous pericytes (MCPs) and aortic SMC using immunofluorescence (IF) staining ( Figure 2-figure supplement 1D). ...

... Following this, we monitored the recruitment of arrestin3 to the Y 1 R and the disulfidedeficient variants. Interestingly, no arrestin recruitment was detected in the disulfide deficient variants at 10 µM NPY, even though the Y 1 R is generally known to have a high affinity to arrestin3 [42] and showed half-maximal recruitment at 8 nM NPY. Accordingly, loss of the disulfide resulted in a >1220-fold loss in functional affinity for this pathway ( Figure 5D). ...

... Recently, we reported on a peptide-templated acyl transfer reaction using short N-terminal peptide tags, carrying a coiled-coil motif, to introduce fluorescent reporters at distinct time points to monitor GPCR trafficking in mammalian cells. [25,26] Coiled-coil motifs provide an interface, which displays a defined pattern of ionic and hydrophobic amino acids, allowing the selective interaction with a complementary peptide sequence. For covalent peptide-templated labeling, the acceptor peptide is genetically fused to the extracellularly exposed N-terminus of a GPCR, equipped with an N-terminal cysteine residue, and the complementary peptide probe carries a reporter by thioester linkage. ...

... A number of naturally occurring mutations were found to alter signaling pathways of GPCRs (52). For example, substitution of a TM6 residue of α1-adrenergic receptor led to constitutive G protein activity (53); a leucine-to-glutamine mutation in the TM3 helix of cysteinyl-leukotriene receptor 2 strongly drove G q/11 signaling (54); and mutations in the C terminus of several class A GPCRs, including apelin receptor and neuropeptide Y4 receptor, diminished β-arrestin recruitments (55,56). Although many genetic variations of GPCRs have been detected (34), the mechanisms governing signal bias are poorly understood. ...

... For covalent peptide-templated labeling, the acceptor peptide is genetically fused to the extracellularly exposed N-terminus of a GPCR, equipped with an N-terminal cysteine residue, and the complementary peptide probe carries a reporter by thioester linkage. [25,27] Parallel alignment of both peptides triggers an acyl transfer reaction, which leads to covalent modification of the respective GPCR. ...