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• W770492871 abstract "Membrane fusion events between various intracellular compartments in eukaryotic cells are mediated by two conserved protein families: SNARE- and Sec1/Munc18 (SM)-proteins. The SNARE proteins syntaxin1, SNAP-25, and synaptobrevin2 play a central role during fusion of synaptic vesicles with the plasma membrane. Syntaxin1 and SNAP-25 are located in the plasma membrane, whereas synaptobrevin2 resides on synaptic vesicles. Their assembly into a membrane-bridging ternary SNARE complex is believed to drive fusion. SM-proteins interact with SNARE-proteins but the molecular basis for this interaction is not entirely understood. Munc18a binds the cytosolic domain of syntaxin1a in a so called closed conformation. A binding mode distinct from that of Munc18a/syntaxin1a appears to govern the interaction of several other SM-proteins (i.e. Munc18c, Sly1, Vps45) with their cognate syntaxins. In these complexes the far N-terminal region of syntaxin binds to the SM-protein. In the first part of this thesis it is shown that Munc18a binds simultaneously to the closed conformation of syntaxin1a and to the N-terminal peptide of syntaxin1a by ITC. In addition, residual electron density on the outer surface of domain 1 of Munc18a was uncovered, a finding that had been overlooked until now. Re-refinement of the Munc18a/syntaxin1a-structure improved the electron density within this region, and residues 2 9 of syntaxin1a could be modelled. A second SM-protein/syntaxin-pair was also investigated. It was observed that the N-terminal peptide of syntaxin 16 binds to the SM-protein Vps45, while the remainder of syntaxin 16, probably in a closed conformation strongly enhances the affinity of the interaction. Collectively these data indicate that SM-proteins interact with their cognate syntaxins via a conserved binding mechanism. Two regions of syntaxin appear to cooperatively bind Munc18a. Next, the role of Munc18a in controlling SNARE complex assembly was investigated. It has previously been established, that Munc18a binds syntaxin1a and thereby blocks SNARE-complex assembly in vitro. However, how syntaxin1a can escape the tight grip of Munc18a, thus enabling its participation in SNARE complex formation remains unclear. Here it is demonstrated, that the interaction of Munc18a with the N-terminal peptide of syntaxin1a is essential for the inhibition of SNARE-complex formation. Removal of the N-terminal peptide of syntaxin1a, and either point mutations in the peptide, or in the Munc18a binding site, allowed for SNARE complex formation of Munc18a-bound syntaxin1a. These results suggest a conformational change in the Munc18a/syntaxin1a-complex. In the third section, the interaction of Munc18 and syntaxin1 and the role of Munc18 in SNARE-complex assembly in the choanoflagellate Monosiga brevicollis, a unicellular organism believed to be the closest known relative of animals, was investigated. The results indicate that not only is the binding of Munc18 to the N-terminal peptide and the closed conformation of syntaxin1 conserved, but also the regulative function of Munc18 in controlling SNARE-complex assembly in chaonoflagellates. Furthermore using light- and electron microscopy it was shown that Monosiga brevicollis appears to possess a secretion apparatus localized to the apical region of the cell." @default.
• W770492871 created "2016-06-24" @default.
• W770492871 creator A5072644672 @default.
• W770492871 date "2022-02-20" @default.
• W770492871 modified "2023-09-24" @default.
• W770492871 title "Vergleichende Untersuchungen zur Regulation der SNARE-Komplexbildung durch Sec1/Munc18-Proteine" @default.
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