Systematic detection and structural characterization of functional proteoform groups
Supervision
Isabell Bludau
UKHD, 1st Supervisor
Kathryn Lilley
UCAM, 2nd Supervisor
Objectives
This project aims to develop a systematic approach for detecting and structurally characterizing functional proteoform groups. By integrating comprehensive multi-omics datasets, the study will investigate how alternative proteoforms influence protein structure and interaction networks. The focus will be on profiling proteoform diversity across various brain tumor types to uncover mechanistic insights with diagnostic and therapeutic relevance
Methodology
The project will utilize peptide-level quantitative proteomics data to identify functional proteoform groups based on peptide co-variation patterns. Structural properties of these proteoforms will be inferred using deep learning-based protein structure prediction tools such as AlphaFold and AlphaFold-Multimer. In parallel, a prioritization strategy will be developed to identify genomic alterations that influence proteoform expression and structural features, enabling their assessment as candidate biomarkers or drug targets.
Required skills
Strong programming skills; Background knowledge in molecular biology;Good command of English; Experience in large-scale ‘omics’ data analysis is a plus.
Expected Results
The project will deliver a computational workflow for the systematic detection and structural analysis of functional proteoform groups using multi-omics data. Applied to different brain tumor subtypes, the tool is expected to improve tumor classification and provide novel insights into the functional roles of alternative proteoforms in tumorigenesis. The approach will also support the identification of new diagnostic and therapeutic targets and will be shared openly with the scientific community.
Planned Secondments
Host: UCAM (Kathryn Lilley), Duration: 2 Months; When: Year 1, Goal: Investigate subcellular proteoform localization.
Host: KTH (Lukas Käll), Duration: 1 Month; When: Year 2, Goal: Benchmarking strategy for proteoform identification.
Host: IMB (Katja Luck), Duration: 1 Month; When: Year 3, Goal: Explore proteoform-specific interaction interfaces.
Enrolment in doctoral programs
DKFZ International PhD Program, with the PhD degree awarded by Heidelberg University.
References
Bludau, I., Frank, M., Dörig, C. et al. Systematic detection of functional proteoform groups from bottom-up proteomic datasets. Nat Commun 12, 3810 (2021). https://doi.org/10.1038/s41467-021-24030-x
Bludau I, Willems S, Zeng WF, et al. The structural context of posttranslational modifications at a proteome-wide scale. PLoS Biol. 2022;20(5):e3001636. Published 2022 May 16. doi:10.1371/journal.pbio.3001636
Bludau, I., Aebersold, R. Proteomic and interactomic insights into the molecular basis of cell functional diversity. Nat Rev Mol Cell Biol 21, 327–340 (2020). https://doi.org/10.1038/s41580-020-0231-2