40 research outputs found
Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6
No full textHerein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α-helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs
A programmable “build–couple” approach to the synthesis of heterofunctionalized polyvalent molecules
No full textGanciclovir derivatives for modulating innate and adaptive immunity and for use in immunotherapy
No full textCompositions and methods for modulating innate and adaptive immunity and for use in immunotherapy are disclosed. In particular, the invention relates to novel ganciclovir derivatives and methods of using them for the treatment of immune-related disorders, including inflammation, autoimmunity, and infections, and neurological disorders, and cancer.LMN
Elucidating the Role of Site-Specific Nitration of α-Synuclein in the Pathogenesis of Parkinson’s Disease via Protein Semisynthesis and Mutagenesis
No full text
Synthesis of N<sub>3</sub>S, N<sub>3</sub>O, N<sub>2</sub>S<sub>2</sub>, N<sub>2</sub>O<sub>2</sub>, N<sub>2</sub>SO and N<sub>2</sub>OS porphyrins with one meso-unsubstituted carbon
No full textA simple straightforward synthesis of N3S, N2S2, N2O2, N2SO and N2OS porphyrins and an improved method for the synthesis of an N3O porphyrin with one meso-unsubstituted carbon atom are reported from readily available precursors. The reactivity of the meso-unsubstituted carbon atom was demonstrated by carrying out bromination followed by Heck coupling reactions
Elucidating the Role of Site-Specific Nitration of alpha-Synuclein in the Pathogenesis of Parkinson's Disease via Protein Semisynthesis and Mutagenesis
No full textParkinsons disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneuronal inclusions consisting of aggregated and post-translationally modified a-synuclein (a-syn). Despite advances in the chemical synthesis of a-syn and other proteins, the generation of site-specifically nitrated synthetic proteins has not been reported. Consequently, it has not been possible to determine the roles of nitration at specific residues in regulating the physiological and pathogenic properties of a-syn. Here we report, for the first time, the site-specific incorporation of 3-nitrotyrosine at different regions of a-syn using native chemical ligation combined with a novel desulfurization strategy. This strategy enabled us to investigate the role of nitration at single or multiple tyrosine residues in regulating a-syn structure, membrane binding, oligomerization, and fibrils formation. We demonstrate that different site-specifically nitrated a-syn species exhibit distinct structural and aggregation properties and exhibit reduced affinity to negatively charged vesicle membranes. We provide evidence that intermolecular interactions between the N- and C-terminal regions of a-syn play critical roles in mediating nitration-induced a-syn oligomerization. For example, when Y39 is not available for nitration (Y39F and Y39/125F), the extent of cross-linking is limited mostly to dimer formation, whereas mutants in which Y39 along with one or multiple C-terminal tyrosines (Y125F, Y133F, Y136F and Y133/136F) can still undergo nitration readily to form higher-order oligomers. Our semisynthetic strategy for generating site-specifically nitrated proteins opens up new possibilities for investigating the role of nitration in regulating protein structure and function in health and disease.LMN
A New Caged-Glutamine Derivative as a Tool To Control the Assembly of Glutamine-Containing Amyloidogenic Peptides
No full textWe present the design, synthesis, and characterization of a novel photocaged glutamine derivative (modified on the side chain of glutamine), and describe its use in enhancing peptide stability and solubility. Our results demonstrate that this approach can be used to develop molecular switches to control the folding and β-sheet formation of amyloidogenic peptides.LMN
A New Caged‐Glutamine Derivative as a Tool To Control the Assembly of Glutamine‐Containing Amyloidogenic Peptides
No full textMotives And Subjects In Fictitious Collections Of Erotic And Mimetic Letters Written In Imperial Greece
No full textDolgozatomban a fiktív levelek egy szűkebb csoportját vizsgáltam. Ezeket a leveleket J. SYKUTRIS (Epistolographie, in: RE Suppl. 5, 1931, 185-220) a mimétikus és erotikus levelek közé sorolja. Bár több szerző nevéhez kötődik ilyen gyűjtemény, összesen öt alkotó gyűjteménye maradt ránk: Klaudios Ailianosé, Alkiphróné, Philostratosé, Aristainetosé és Theophylaktos Simokat(t)ésé.
A vizsgálatba azért vontam be mind az öt fennmaradt gyűjteményt, mert bár az egyes szerzők gyűjteményeiről már születtek tanulmányok vagy akár monográfiák is, azonban ezek között az alkotások között annyira szoros kapcsolat van, hogy érdemesnek tartottam e gyűjtemények összehasonlító vizsgálatát, és a közös, ill. az eltérő vonásokat is keresni. E módszer választásának helyességében az is megerősített, hogy NÉMETH A. (Császárkori fiktív levelek, Kísérlet az uralkodók és filozófus-gyógyítók fiktív leveleinek újszerű vizsgálatára, Budapest, 2005, ELTE) vizsgálata is új eredményeket hozott. A szakdolgozat szerzője azokat a leveleket vizsgálta együtt, amelyeket ismeretlen szerzők írtak híres, történeti személynek tekintett személyek bőrébe bújva (a legtöbb esetben szintén a császárkor első századaiban).
In my thesis I have examined a restricted group of fictitious letters. These letters are included in the group of mimetic and erotic letters by J. SYKUTRIS (Epistolographie, in: RE Suppl. 5, 1931, 185-220). Though such collections can be ascribed to the names of several authors, collections of five authors in all have come down to us (Aelian´s Rustic Letters, Alciphron, Philostratus, Aristainetos, Theophylaktus).
The reason for my including all the five surviving collections in the investigation is that, although papers or even monographs have already been published on the collections of individual authors, the relationship between these writings is so close that I found it convenient to perform a comparative analysis of these collections, trying to find both the common and the divergent features. In choosing this method I have found confirmation in the fact that the investigation of NÉMETH A. (Császárkori fiktív levelek, Kísérlet az uralkodók és filozófus-gyógyítók fiktív leveleinek újszerű vizsgálatára, Budapest, 2005, ELTE) has yielded new results. The author of the thesis examined a set of letters written by unknown authors disguised as famous historical personages (in most cases also in the first centuries of the imperial age)
