Geiss-Friedlander, Ruth, Dr.*
- 2009 - present: Independent research group leader at the Department of Molecular Biology, Göttingen
- 2004 - 2008: Postdoctoral fellow in the lab of Prof. Dr. Frauke Melchior, at the Biochemistry I Department, Göttingen, Germany
- 1999-2004: PhD thesis in the laboratory of Prof. Dr. Thomas Sommer, Max-Delbrück-Centre for Molecular Medicine, Berlin, Germany
- 1996-1998: MSc studies in the laboratory of Prof. Dr. Yossi Orly, Faculty of Science, Department of Structural and Molecular Biochemistry, Hebrew University, Jerusalem, Israel
Major Research Interests
Proteolytic enzymes and ubiquitin-like proteins: biochemical properties, regulation and roles in cell signaling.
Proteolytic enzymes constitute 1-5% of the human genome, function both as degredative enzymes and as irreversible post-translational modifiers in a process known as limited proteolysis. Recent proteomics data estimate that more than 30% of all proteins undergo limited proteolysis, apart from the removal of methionine, and signal peptides. The exposure or removal of parts of a polypeptide chain can then lead to a variety of outcomes, including changes in protein interactions, stability, catalytic activity or even cellular localization of the processed target protein.
While many proteases are redundant in their activity and selectivity, only few can cleave a peptide bond following a proline residue because of its ridged ring structure. Members of the S9B/DPPIV family are serine amino peptidases with the unique ability to cleave off such a bond. Four active members of this family are known. DPPIV and FAP are membrane-bound cell-surface peptidases, whereas DPP8 and DPP9 are intra-cellular. DPP8 and DPP9 are linked to various important physiological pathways, including antigen presentation, cell survival, apoptosis, cell adhesion and migration. Recently a nock-in mouse with a serine to alanine point mutation in the DPP9 active site (S729A) was generated. These mice expressing the inactive DPP9 mutant died within 8 to 24 hours after birth. For most of these outcomes- the underlying molecular mechanisms are not understood.
By combining biochemical and cell based assays, we study the regulation and physiological functions of DPP8 and DPP9. Work from our lab showed that DPP9 is the rate limiting peptidase for the degradation of proline-containing peptides in the cytosol. In addition, we identified proline-contaning antigen peptides as natural DPP9 substrates linking DPP9 to antigen processing. Recently we showed that both DPP8 and DPP9 interact in a non-covalent manner with SUMO1, which acts as an allosteric regulator of these peptidases. After identifying interaction surfaces on DPP9 and SUMO1, we used this knowledge to develop allosteric inhibitors for these peptidases, these inhibitors are part of a patent application which was filed by the university of Göttingen. Current work in the lab aims to further study the allosteric regulation of DPP9. In addition, we are screening for DPP8 and DPP9 substrates, as well as for the DPP8 and DPP9 interactome.
Homepage Department/Research Group
Selected Recent Publications
- Strenzke N., Chakrabarti R., Al-Moyed H., Müller A., Hoch G., Pangrsic T., Yamanbaeva G., Lenz C., Pan KT., Auge E., Geiss-Friedlander R., Urlaub H., Brose N., Wichmann C. and Reisinger E. (2016) Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants. EMBO DOI: 10.15252/embj.201694564
** this publication was honoured in the 14th round of GöVIP (Very Important Publications) by the Research Commission of the UMG www.med.uni-goettingen.de/de/content/ueberuns/20315.html
- Justa-Schuch, D., Silva-Garcia, M., Pilla, E., Engelke, M., Kilisch, M., Lenz, C., Möller, U., Nakamura, F., Urlaub, H. and Geiss-Friedlander, R. (2016) DPP9 is a novel component of the N-end rule pathway targeting the Tyrosine Kinase Syk. eLife DOI: 10.7554/eLife.16370.
** this publication was honoured in the 13th round of GöVIP (Very Important Publications) by the Research Commission of the UMG www.med.uni-goettingen.de/de/content/ueberuns/20315.html
- Zhang, H; Maqsudi, S., Rainczuk, A., Duffield, N; Lawrence, J., Keane, FM., Justa-Schuch, D., Geiss-Friedlander, R., Gorrell, MD., Stephens, AN. (2015) Identification of Novel Dipeptidyl Peptidase 9 Substrates by 2D DIGE. FEBS doi: 10.1111/febs.13371.
- Justa-Schuch, D., Möller, U., and Geiss-Friedlander, R. (2014) The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus. Cell. Mol. Life Sci. 71(18): 3611-3626.
- Pilla, E., Kilisch, M., Lenz, C., Urlaub, H., and Geiss-Friedlander, R. (2013) The SUMO1-E67 interacting loop peptide is an allosteric inhibitor of the dipeptidyl peptidases 8 and 9. J Biol Chem 288: 32787–32796
- Pilla, E., Moller, U., Sauer, G., Mattiroli, F., Melchior, F., and Geiss Friedlander, R. (2012) A novel SUMO1-specific interacting motif in Dipeptidyl peptidase 9 (DPP9) that is important for enzymatic regulation. J Biol Chem 287: 44320–44329.