UNIVERSITY OF COLOGNE

Bifunctional Peptite Probes Interfering with the Dynamic Localization of KRas

Ras proteins belong to the family of small GTP-binding proteins and are important nodes in intracellular signaling networks. We developed cell-permeable CaaX-peptides that impair Ras protein localization and hence their biological function as a molecular switch. The peptides combine a cell-penetrating peptide (CPP) with a C-terminal CaaX-motif of Ras proteins. They accumulate to high extent inside cells and exhibit pronounced toxicity to cancerous cells, particularly to KRas mutated pancreatic cancer cells. Within this project we aim to study the disturbed topology of KRas that likely affects protein-lipid and protein-protein interactions important for the early steps of KRas-mediated cellular signaling. 

First Cohort Project: Design of Cell-Permeable Tools to Study Cysteine Prenyalation

Within this project we aim to develop novel tools to study cysteine prenylation, which is mediated in the first step by prenyltransferases. The doctoral candidate will investigate the interaction of cell-permeable peptides with prenyltransferases in cell-free and cellular systems. Techniques applied vary from chemical peptide and recombinant protein synthesis to biophysical (e.g. protein-protein interaction) and cellular (e.g. uptake, cell viability) assays.

Publications

• AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. Salscheider SL, Gerlich S, Cabrera-Orefice A, Peker E, Rothemann RA, Murschall LM, Finger Y, Szczepanowska K, Ahmadi ZA, Guerrero-Castillo S, Erdogan A, Becker M, Ali M, Habich M, Petrungaro C, Burdina N, Schwarz G, Klußmann M, Neundorf I, Stroud DA, Ryan MT, Trifunovic A, Brandt U, Riemer J. EMBO J. 2022 Jul 20:e110784. doi: 10.15252/embj.2022110784. Online ahead of print. PMID: 35859387

• Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery. Noguchi K, Obuki M, Sumi H, Klußmann M, Morimoto K, Nakai S, Hashimoto T, Fujiwara D, Fujii I, Yuba E, Takatani-Nakase T, Neundorf I, Nakase I. Mol. Pharmaceutics 2021, 18, 9, 3290–3301 2021 Aug 8.doi: 10.1021/acs.molpharmaceut.1c00244
• Molecular Plasticity of Crystalline CK2α' Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity. Lindenblatt D, Applegate V, Nickelsen A, Klußmann M, Neundorf I, Götz C, Jose J, Niefind K. J Med Chem. 2021 Jul 29. doi: 10.1021/acs.jmedchem.1c00063. PMID: 34323071

• Recent Advances and Trends in Chemical CPP-Drug Conjugation Techniques. (Review) Gayraud F, Klußmann M, Neundorf I. Molecules. 2021 Mar 13;26(6):1591. doi: 10.3390/molecules26061591. PMID: 3380568

• Interdependence of charge and secondary structure on cellular uptake of cell penetrating peptide functionalized silica nanoparticles. Gessner G, Klimpel A, Klußmann M, Neundorf I, Mathur S. Nanoscale Adv., 2020, 2, 453-462. doi: 10.1039/C9NA00693A

Publications

• Mitochondria shed their outer membrane in response to infection-induced stress. Li X, Straub J, Medeiros TC, Mehra C, den Brave F, Peker E, Atanassov I, Stillger K, Michaelis JB, Burbridge E, Adrain C, Münch C, Riemer J, Becker T, Pernas LF. Science. 2022 Jan 14;375(6577):eabi4343. doi: 10.1126/science.abi4343. Epub 2022 Jan 14. PMID: 35025629

• Cell-permeable CaaX-peptides affect K-Ras downstream signaling and promote cell death in cancer cells. Klimpel A, Stillger K, Wiederstein JL, Krüger M, Neundorf I. FEBS J. 2021 May;288(9):2911-2929. doi: 10.1111/febs.15612. Epub 2020 Nov 7. PMID: 33112492