Université de Strasbourg

Patrick Schultz

Biography - Patrick Schultz

Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS and Inserm, France

Patrick Schultz, USIAS Fellow 2021

In his research, Patrick Schultz focuses on understanding the relationships between the structure and function of multiprotein assemblies regulating DNA transcription and modulating chromatin structure. During his PhD at the University of Strasbourg under the supervision of Professor Pierre Oudet, he studied the structure of chromatin and the appearance of nucleosome-free regions by electron microscopy (EM). During a 16-month internship at European Molecular Biology Laboratory (EMBL Heidelberg, Germany) in Professor Jacques Dubochet's team, he learned that biomolecules must be observed under hydrated conditions by cryo-EM, and that chromatin structure is driven by liquid-liquid phase transitions. Upon his return to Strasbourg, Dr. Schultz used numerical image analysis methods to calculate volumetric models of the molecules of interest at the nanoscale. In collaboration with Charles Mioskowski and Luc Lebeau, he developed amphipathic molecules for the two-dimensional crystallization of proteins. After exploring the architecture of RNA polymerase I, he studied the structure of multi-protein assemblies regulating transcription initiation from single particle EM images. His team, based at the IGBMC, provided the first structural models of the yeast transcription factors TFIIH and TFIID and described the distribution of their subunits.

Two team members, Adam Ben Shem and Gabor Papai, developed innovative purification protocols and exploited advances in cryo-EM to achieve atomic models of biomolecules. The team furthermore elucidated the structure of TFIID as well as its mode of interaction with the promoter DNA. After obtaining the first molecular model of the SAGA co-activator in 2004, they were able to solve its atomic structure in 2020 and show that SAGA shares with TFIID a similar mechanism to deliver the TBP protein and initiate transcription.

Project - Structure of human transcription co-activators

01/07/2021 - 30/06/2023

Transcriptional regulation depends on multisubunit co-activators that convert cell signalling and epigenetic status into transcription pre-initiation complex (PIC) assembly. Co-activators of the SWI/SNF family remodel the structure of chromatin, form a nucleosome-depleted region over the transcription start site and render gene promoters accessible. The SAGA co-activator acetylates histones, removes ubiquitin from histones and loads the TATA-box binding protein onto gene promoters. Our objective is to determine the architecture of these molecular machines in order to understand their mode of action.

The groundbreaking novelty of the proposal is to develop methods to address the structure of rare human complexes involved in transcription regulation, since all the currently available structural information has been obtained on molecular complexes purified from yeast cells. The project team expects to develop methods and optimize conditions for large-scale production of human transcription-co-activators. In particular, they will try to humanize yeast cells to recapitulate molecular interactions. One of the objectives of the project is to develop specifically designed human cell lines to tag the molecules of interest with affinity tags and fluorescent tags to facilitate their purification. An additional objective is to graft natural ligands or engineered antibody fragments to chromatography columns in order to purify co-activators from untagged mouse models of human patients. This will open up the possibility to determine the atomic structure of native complexes.

Currently available yeast structural models of co-activators do not sufficiently explain vertebrate-specific biological questions. Human transcription co-activator complexes, the key focus of this project, are involved in rare neurodegenerative genetic disorders and in cancer development. It is far more relevant - but much more challenging - to purify and study the structure of human complexes, and dedicated technologies will be developed in this proposal. Atomic structures of human co-activators are required to explain the molecular mechanisms of these complexes, understand the role of mutations found in patients and evaluate the action of inhibitors of enzymatic activities or protein-protein interactions. Only a few years ago, solving the structure of a co-activator complex was considered as impossible, but recent advances in single particle cryo-electron microscopy have changed the situation. If we are able to meet the challenge of large-scale purification, atomic-scale information will be made available for complexes relevant for human health.

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