Publication date:

Sept 14th 2020

Postdoc position bridging Tumor Immunology and Proteomics

Immuno-oncology is a promising new area within the field of basic, translational and clinical cancer research and recent years have seen breakthroughs where (otherwise untreatable) patients have been cured by novel immunotherapies. Immuno-oncology focusses on understanding the relationship between the tumor and the patients’ own immune system, with the aim to target the cancer or microenvironment with antibodies or immune cells. Central to this approach is the identification of unique antigens presented by the tumor cells and immunological characterization of the tumor microenvironment (TME). Mass spectrometry provides the much-needed hypothesis-free window to discovery specific and novel tumor antigens, and reveal the intricacies of the tumor immunological landscape. In this position, you will participate in the PMC-UMCU-UU tumor immunology initative, and work alongside immunologists and clinicians in joint efforts, within the strong collaborative network of the immune-oncology research community in Utrecht. A background in proteomics and tumor immunology would be appreciated.

Publication date:

Sept 3rd 2020

PhD position in protein lipidation

Signalling events between proteins, as well as protein localization, are highly and specifically regulated by the post-translational modifications (PTMs) that they can transiently harbour. Of these PTMs, phosphorylation, glycosylation and acetylation have been widely studied and characterized. Protein lipidation, the covalent attachment of a lipid group to a protein, is much less studied, but thought to be equally important. In addition to its well-established important role in fundamental biology, protein lipidation has been associated with multiple neurological diseases, including Huntington’s disease and Alzheimer’s disease.

In this project, you will work at the interface of chemistry and biology. You will develop new chemical biology and proteomics tools to study the regulation of protein lipidation, focusing on S-palmitoylation, aiming to reveal how these modifications affect brain proteins, especially those that are linked to neurological diseases. You have ideally a background in chemical biology, hands-on MS experience is preferred, but not essential at the start.

Publication date:

May 4th 2020

PhD position in GPCR signalling

G Protein coupled receptors (GPCRs) are promising targets for treatment of cancer, as well as immune and inflammatory diseases. Next to small molecules, antibody therapeutics are recently found to modulate GPCR function with better specificity and longer lasting effects.

In this project, you will use combined techniques in mass spectrometry and cancer biology to study the mechanisms of novel antibody/nanobody therapeutics and bispecifics targeting GPCRs and GPCR oligomerisation. In this inter-disciplinary project bridging mass spectrometry, cell biology, and antibody/nanobody engineering, you will also become part of an extended research network collectively aimed at revealing the intricacies of GPCR signalling and rational perturbations for therapy. This ‘MAGNETIC’ consortium is funded by the NWO-ENW-PPS scheme, to develop the next-generation of GPCR-targeting pharmaceuticals. Applicants with prior knowledge in cell signalling are preferred; prior hands-on MS experience is not critical at the start.

Publication date:

April 21st 2020

3 PostDoc positions on Epic-XS projects

Are you interested in developing a cutting-edge research program focused on developing and applying bioanalytical and biochemical approaches to investigate biological and disease processes?

General

Within the European consortium Epic-XS (https://epic-xs.eu) three different 2-year post-doctoral positions are available at Utrecht University, placed within the Heck-lab (https://hecklab.com), Altelaar-lab (https://altelaarlab.com/), and the Scheltema-lab (https://scheltemalab.com). The research emphasizes on the development of advanced mass spectrometry-based methods to address questions in proteomics and structural biology. The laboratory houses an excellent infrastructure, including a dozen state-of-the-art mass spectrometers, advanced separation technologies, bioinformatics, and laboratories for cell culture, biochemistry and molecular biology. The research group is vibrant and houses over 15 nationalities – Utrecht is a great place to be!

For all positions, the work is embedded in the European Proteomics program Epic-XS and participation in international meetings for this consortium is expected. The aim is to implement the developed technologies into the access sites, promoting collaborations.

Position 1: Mass spectrometry driven structural investigations (https://scheltemalab.com)

The Scheltema laboratory focusses on the development and application of cross-linking mass spectrometry (XL-MS) to study protein-protein interactions. This technology utilizes small and agile reagents that covalently connect amino acids in close proximity. After proteolytic digestion, mass spectrometry can identify the connected amino acids. From these identifications distances constraints are derived that can be placed in in protein 3D structures, either known or directly predicted using this information. The structural details, at a resolution in the range of a few nanometers, allow resolving interaction interfaces between proteins. This can be done either in-vitro or in-situ in a close-to-native environment, making XL-MS an incredibly powerful approach for cell and structural biology.

For this position, you will join a team of dedicated researchers combining expertise in bioinformatics, biochemistry, mass spectrometry, and structural modeling on a variety of systems and organisms to answer cutting-edge questions in biological sciences. You are expected to apply size-exclusion chromatography and sucrose gradient ultracentrifugation to purify interesting protein assemblies, perform the cross-linking and mass spectrometry assays, perform data analysis and integrate the data into structural models. As part of the European Proteomics program Epic-XS you will interact and collaborate with international researchers and develop new methods for cross-linking mass spectrometry.

Recent illustrative work

1. P Albanese, S Tamara, G Saracco, C Pagliano, RA Scheltema (2020) How paired PSII-LHCII supercomplexes mediate the stacking of plant thylakoid membranes unveiled by integrative structural mass-spectrometry Nature Communications 11, 1361
2. O Klykov, C van der Zwaan, AJR Heck, AB Meijer, RA Scheltema (2020) Missing regions within the molecular architecture of human fibrin clots structurally resolved by XL-MS and integrative structural modeling Proceedings of the National Academy of Sciences 17 (4), 1976-1987
3. B Steigenberger, RJ Pieters, AJR Heck, RA Scheltema (2019) PhoX: An IMAC-Enrichable Cross-Linking Reagent ACS Central Science 5 (9), 1514-1522

Position 2: Clinical proteomics (https://altelaarlab.com/)

Translational proteomics has made significant progress in recent years with improved protocols for the analysis of clinically important samples such as patient biopsy tissue material and different types of liquid biopsies. The analysis of patient tissue material allows the investigation of the disease state and the treatment response directly in the native in vivo environment and thereby provides valuable molecular disease information with high translational capacity. To make translational proteomics a main technology in clinical settings, several challenges need to be addressed. Here, we will focus on tissue biopsies, as the life in vivo setting, and extracellular vesicles (EVs), which potentially contain biomarkers for diagnosis and prognosis of disease conditions. Proteomics approaches will consist of high-end shotgun proteomics and targeted proteomics (e.g. DIA and SRM).

For this position, we seek a highly motivated biochemist or analytical chemist with proven expertise in mass spectrometry and clinical proteomics. You will join a team of dedicated researchers combining expertise in biochemistry, analytical chemistry, mass spectrometry and bioinformatics on a variety of systems to answer pressing clinical questions. As part of the European Proteomics program Epic-XS you will interact and collaborate with international researchers and develop new methods to translate proteomics results in clinically relevant information.

Recent illustrative work

1. Schmidlin T, Debets DO, van Gelder CAGH, Stecker KE, Rontogianni S, van den Eshof BL, Kemper K, Lips EH, van den Biggelaar M, Peeper DS, Heck AJR, Altelaar M. (2019) High-Throughput Assessment of Kinome-wide Activation States. Cell Systems 9(4):366-374.
2. Rontogianni S, Synadaki E, Li B, Liefaard MC, Lips EH, Wesseling J, Wu W, Altelaar M. (2019) Proteomic profiling of extracellular vesicles allows for human breast cancer subtyping. Communications Biology 2:325.
3. Zagorac I, et al. (2018) In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer. Nature Communications 9(1), 3501.

Position 3: Native and top-down proteomics (https://hecklab.com)

In recent years we have been developing new mass analyzers and new fragmentation techniques targeted towards the direct analysis of intact proteins and protein complexes by native and top-down proteomics. Such analyses on the one hand allow us to directly probe stoichiometries and structures of large protein assemblies, like viruses and ribosome particles, on the other they make it possibly to identify and quantify distinct proteoforms of proteins highly modified by post-translational modifications such as phoshoproteins and (plasma) glycoproteins. Introducing charge detection single particle mass spectrometry and ECD and UVPD fragmentation on Orbitrap platforms has provided us with an unprecedented toolbox to discover so far little explored relevant parts of the proteome.

For this position, we seek a highly motivated biochemist or analytical chemist with proven expertise in biomolecular mass spectrometry. Having your own project, you will join a team of dedicated researchers combining expertise in bioinformatics, engineering and instrument development, biochemistry, analytical chemistry, and structural biology, and work on a variety of systems and organisms to answer cutting-edge questions in biological sciences. As part of the European Proteomics program Epic-XS you will interact and collaborate with international researchers and develop new methods for native mass spectrometry and top-down proteomics.

Recent illustrative work

1. TP Wörner, J Snijder, A Bennett, M Agbandje-McKenna, AA Makarov, AJR Heck (2020) Resolving heterogeneous macromolecular assemblies by Orbitrap-based single-particle charge detection mass spectrometry Nature Methods 17(4), 395-398.
2. JF Greisch, S Tamara, RA Scheltema, HWR Maxwell, RD Fagerlund, PC Fineran, S Tetter, D Hilvert, AJR Heck (2019) Expanding the mass range for UVPD-based native top-down mass spectrometry Chemical Science 10(30), 7163-7171
3. M van de Waterbeemd, KL Fort, D Boll, M Reinhardt-Szyba, A Routh, AA Makarov, AJR Heck (2017) High-fidelity mass analysis unveils heterogeneity in intact ribosomal particles Nature Methods 14(3), 283-286.