Investigation of the properties of Acyl protein thioesterases and their role in Ras depalmitoylation
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Date
2017
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Abstract
Es konnte gezeigt werden, dass die Inhibition des Proteins Acyl Protein Thioesterase (APT) die Lokalisierung von palmitoylierten Ras Proteinen derart verändern kann, dass eine Reduzierung der onkogenen Ras Aktivität beobachtet wird. Die genaue physiologische Rolle von APT ist allerdings weiterhin unklar, da sowohl weitere palmitoylierte Proteine, als auch (Lyso-) Phospholipide und Prostaglandin Glycerin Ester als Substrate von APT beschrieben wurden.
Die hier vorliegende Arbeit liefert, durch Untersuchung der Interaktionen verschiedener Substrate, Liganden und Inhibitoren mit APT, neue Erkenntnisse bezüglich möglicher zellulärer Aufgaben von APT. Die gewonnenen Resultate helfen zu bestimmen, welche Substrate von APT bevorzugt werden, wie eine Substratspezifität erreicht wird und wie sich APT im Laufe der Evolution in verschiedenen eukaryotischen Spezies entwickelt hat.
It was shown that inhibition of the activity of Acyl Protein Thioesterase (APT) proteins by palmostatin B could change the localization of the palmitoylated oncogene Ras and lead to a down-regulation of Ras signaling. Besides this particular activity of APT several other protein targets of APT were described, some of them as specific substrates for one of the two isoforms. Furthermore, APT activity was also linked to non-protein substrates like (lyso-)phospholipids and prostaglandin glycerol esters. Still, the real physiological function of the conserved and ubiquitously expressed APT proteins remains elusive. This thesis provides new insights into possible physiological roles of APT and its isoforms by focusing on the interaction of different substrates, ligands and inhibitors with APT proteins. The results help to answer the question what kind of substrates APT prefers, how substrate specificity is achieved and how APTs might have evolved in the different eukaryotic species.
It was shown that inhibition of the activity of Acyl Protein Thioesterase (APT) proteins by palmostatin B could change the localization of the palmitoylated oncogene Ras and lead to a down-regulation of Ras signaling. Besides this particular activity of APT several other protein targets of APT were described, some of them as specific substrates for one of the two isoforms. Furthermore, APT activity was also linked to non-protein substrates like (lyso-)phospholipids and prostaglandin glycerol esters. Still, the real physiological function of the conserved and ubiquitously expressed APT proteins remains elusive. This thesis provides new insights into possible physiological roles of APT and its isoforms by focusing on the interaction of different substrates, ligands and inhibitors with APT proteins. The results help to answer the question what kind of substrates APT prefers, how substrate specificity is achieved and how APTs might have evolved in the different eukaryotic species.
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Acyl protein thioesterase, APT, Ras, Depalmitoylation, Structural analysis, Assay development