@article{WolffSchuelerGastetal.2020, author = {Wolff, Martin and Sch{\"u}ler, Anja and Gast, Klaus and Seckler, Robert and Evers, Andreas and Pfeiffer-Marek, Stefania and Kurz, Michael and Nagel, Norbert and Haack, Torsten and Wagner, Michael and Thalhammer, Anja}, title = {Self-Assembly of Exendin-4-Derived Dual Peptide Agonists is Mediated by Acylation and Correlated to the Length of Conjugated Fatty Acyl Chains}, series = {Molecular pharmaceutics}, volume = {17}, journal = {Molecular pharmaceutics}, number = {3}, publisher = {American Chemical Society}, address = {Washington}, issn = {1543-8384}, doi = {10.1021/acs.molpharmaceut.9b01195}, pages = {965 -- 978}, year = {2020}, abstract = {Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.}, language = {en} } @article{WolffSchuelerGastetal.2020, author = {Wolff, Martin and Sch{\"u}ler, Anja and Gast, Klaus and Seckler, Robert and Evers, Andreas and Pfeiffer-Marek, Stefania and Kurz, Michael and Nagel, Norbert and Haack, Torsten and Wagner, Michael and Thalhammer, Anja}, title = {Self-Assembly of Exendin-4-Derived Dual Peptide Agonists is Mediated by Acylation and Correlated to the Length of Conjugated Fatty Acyl Chains}, series = {Molecular pharmaceutics}, volume = {17}, journal = {Molecular pharmaceutics}, number = {3}, publisher = {American Chemical Society}, address = {Washington}, issn = {1543-8384}, doi = {10.1021/acs.molpharmaceut.9b01195}, pages = {965 -- 978}, year = {2020}, abstract = {Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.}, language = {en} } @article{CuiSchlesingerSchoenhalsetal.2016, author = {Cui, Huanhuan and Schlesinger, Jenny and Schoenhals, Sophia and Toenjes, Martje and Dunkel, Ilona and Meierhofer, David and Cano, Elena and Schulz, Kerstin and Berger, Michael F. and Haack, Timm and Abdelilah-Seyfried, Salim and Bulyk, Martha L. and Sauer, Sascha and Sperling, Silke R.}, title = {Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA}, series = {Nucleic acids research}, volume = {44}, journal = {Nucleic acids research}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0305-1048}, doi = {10.1093/nar/gkv1244}, pages = {2538 -- 2553}, year = {2016}, abstract = {DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.}, language = {en} } @article{SchroederPreikschatGarnatzHaacketal.1996, author = {Schr{\"o}der-Preikschat, Wolfgang and Garnatz, Thomas and Haack, Ute and Sander, Michael}, title = {Experience made with the design and development of a message-passing kernel for a dual-processor-node parallel computer}, year = {1996}, language = {en} } @inproceedings{WiesnerBarknowitzFlorianetal.2015, author = {Wiesner, Melanie and Barknowitz, Gitte and Florian, Simone and Haack, Michael and Lehmann, Carsten and Lippmann, Doris and Mewis, Inga and Schumacher, Fabian and Brigelius-Floh{\´e}, Regina and Schreiner, Monika and Glatt, Hansruedi}, title = {Pak Choi Fed to Mice: Formation of DNA Adducts and Influence on Xenobiotic-Metabolizing Enzymes}, series = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY}, volume = {388}, booktitle = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, pages = {S68 -- S68}, year = {2015}, language = {en} }