1 PhD project offered in the IPP winter call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

Protein-protein interactions (PPIs) are essential for the proper functioning of most if not all cellular processes. While experimental methods can map PPIs at high throughput, these can only tell us if two proteins interact with each other but not how. This lack in structural information hinders the use of protein interaction data to study physiological and pathological molecular mechanisms. The Luck lab develops and applies computational and experimental approaches to structurally annotate the human protein interactome. More specifically, we build pipelines using AlphaFold and in-house developed machine learning tools to predict protein-protein interaction interfaces and perform in high throughput protein interaction testing in combination with site-directed mutagenesis to validate interface predictions. We have successfully applied these techniques to discover novel protein interaction interfaces functioning in mRNA splicing, piRNA biogenesis, and DNA replication. We further investigate how mutations associated with neurodevelopmental disorders disrupt discovered interfaces and lead to disease.

PhD Project: Integrative structural proteomics for the mapping of protein interaction interfaces

Structural proteomics is an exciting area of research where the power of mass spectrometry is explored to derive structural information on single proteins and protein complexes. The goal of the PhD project is to develop experimental and potentially also computational pipelines that employ structural proteomics approaches in combination with protein complex modelling to map protein interaction interfaces at scale. We have generated a reference set of known and structurally resolved PPIs that we use to build experimental pipelines using crosslinking and covalent labelling mass spectrometry to generate information on how these proteins interact with each other. Using available structural data, these pipelines can be evaluated and further improved. Once the pipelines are established they will be applied to study cellular mechanisms in response to proteotoxic or/and genotoxic stresses. As part of the project, the PhD candidate will employ various state-of-the-art molecular and cell biology techniques in collaboration with the Proteomics Core Facility at IMB to establish protocols. It is furthermore desired that the PhD candidate has interest in conducting data analysis and integration with structural data using python programming to aid in the development of computational pipelines relevant to the project. No prior computational skills but good analytical thinking and an interest in systems approaches to biological research are required.

If you are interested in this project, please select Luck as your group preference in the IPP application platform.

Publications relevant to this project

Lee CY, Hubrich D, Varga JK, Schäfer C, Welzel M, Schumbera E, Djokic M, Strom JM, Schönfeld J, Geist JL, Polat F, Gibson TJ, Keller Valsecchi CI, Kumar M, Schueler-Furman O, Luck K (2024) Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. Mol Syst Biol, 20:75-97 Link

Luck K, Kim DK, Lambourne L, Spirohn K, …, Hill DE, Vidal M, Roth FP, Calderwood MA (2020) A reference map of the human binary protein interactome. Nature 580:402-408 Link

Ebersberger S, Hipp C, Mulorz MM, Buchbender A, Hubrich D, Kang HS, Martínez-Lumbreras S, Kristofori P, Sutandy FXR, Llacsahuanga Allcca L, Schönfeld J, Bakisoglu C, Busch A, Hänel H, Tretow K, Welzel M, Di Liddo A, Möckel MM, Zarnack K, Ebersberger I, Legewie S, Luck K, Sattler M, König J (2023) FUBP1 is a general splicing factor facilitating 3' splice site recognition and splicing of long introns. Mol Cell, 83:2653-2672 Link

Sinz A (2018) Cross-linking/Mass Spectrometry for Studying Protein Structures and Protein-Protein Interactions: Where Are We Now and Where Should We Go from Here?Angew Chemie Intl, 57:6390-96 Link

Arroyo M, Casas-Delucchi CS, Pabba MK, Prorok P, Pradhan SK, Rausch C, Lehmkuhl A, Maiser A, Buschbeck M, Pasque V, Bernstein E, Luck K, Cardoso MC  (2024) Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome. Nucleic Acids Res, 27:gkae734 Link