PhD student in the Haass Lab (SPP/SPPL) from April 2006 until Spring 2009:
|PhD topic||Functional and structural analysis of Signal Peptide Peptidase-like proteases.|
|Thesis adviser||PD. Dr. Regina Fluhrer|
|Subject||Presenilin, the active subunit of the γ-secretase complex (Wolfe et al., Nature, 1999), Signal Peptide Peptidase (SPP) (Weihofen et al., Science, 2002), and SPP-like proteases (SPPL’s) (Krawitz et al., JBC, 2005) belong to the family of intramembrane cleaving GXGD-type aspartyl proteases (Steiner et al., NCB, 2000). γ-secretase liberates in the final step of Amyloid Precursor Protein (APP) processing Aβ, a hallmark of Alzheimer’s disease pathology (Aguzzi and Haass, EMBO, 2002). Since SPP and its homologues do not need additional cofactors for activity (Weihofen et al., Science, 2002) unlike it has been shown for γ-secretase (Edbauer et al., NCB, 2003), it might be easier to understand the mechanism of GXGD-type proteases by studying SPP / SPPL proteases. It was recently shown in the lab that Tumour Necrosis Factor alpha (TNFα) is a substrate for the SPP homologues SPPL2a and SPPL2b (Fluhrer et al., NCB, 2006). SPPL2b cleaves TNFα within its hydrophobic TM by using an at least dual cleavage mechanism. There is evidence that the intracellular fragments of substrates that are subject of intramembrane proteolysis may trigger a specific cellular response (Friedmann et al., NCB, 2006; Ilagan and Kopan, Cell, 2007; Zhang et al., PNAS, 2007). The PhD project includes the search for new substrates for SPP and its homologues using cell culture and in vitro studies. Another goal is to learn more about the biochemical characteristics of the proteolytic mechanism using functional and structural analysis.|
|Funding||The PhD project was funded by the DFG (HA 1737/11-1) - project: “Mechanisms and function of intramembrane proteolysis by the gamma secretase homologous signal-peptide peptidase-like proteins” and the BaCaTeC – Project: “Structural analysis of SPPL3, a gamma secretase-like intramembrane cleaving GxGD protease.”
Lucas Martin was member of the international graduate program "Protein dynamics in health and disease" in the Elite Network Bavaria.
Now Postdoc at Bayer Schering Pharma AG, Berlin.