Lecture
Reedijk Symposium 2024: Exploring the Nanomachinery and Substrate Functions of Mycobacterial Type VII Secretion Systems
- Date
- Friday 22 November 2024
- Time
- Location
-
Lecture Hall
Einsteinweg 57
2333 CC Leiden - Room
- C1
Abstract
Tuberculosis is a highly infectious respiratory disease caused by various strains of mycobacteria, responsible for 1.5 million deaths worldwide annually. The secretion of proteins through type VII secretion systems (T7SSs) plays a crucial role in the survival strategy of mycobacteria within the host. T7SSs are complex nanomachines embedded in the mycobacterial cell envelope. Five paralogous type VII secretion machines export more than 200 proteins that either compromise the immune system or facilitate the uptake of nutrients.
We have determined the first high-resolution structure of a stable core complex of one of these secretion nanomachines, revealing for the first time the intricate network of interactions between various components within the mycobacterial cell envelope. This structural information, combined with recent advances in the molecular biology of type VII secretion systems and their secreted effector proteins, has provided new insights into the inner workings of type VII secretion machineries.
In this seminar, I will present our structural model of the mycobacterial T7SS, highlight the mechanistic implications of our findings, and discuss the transport model derived from our study. Additionally, I will share our research on the secreted proteins involved in nutrient acquisition. Together, these insights set the stage for new strategies to target pathogenic mycobacteria.
Biography
Dr. Sebastian Geibel (1977) studied Biochemistry at the Free University of Berlin from 2003-2006. As PhD student in the group of Prof. Wolfram Saenger in Berlin (2006-2009) he pursued structure function studies on the DNA replication mechanism of broad host range plasmids. His postdoctoral research in the group of Prof. Gabriel Waksman (Birkbeck College, London; 2010-2014) has had a major impact on the elucidation of the assembly and secretion mechanisms of adhesive pili, which are employed by Uropathogenic Escherichia coli to bind and invade epithelial cells of the urinary tract.
In 2014, he set up his research group at the University of Würzburg (Germany) to investigate type VII secretion systems (T7SS). These systems play major roles in the pathogenicity of Mycobacterium tuberculosis, the main causative agent of tuberculosis, and of the human opportunistic pathogen Staphylococcus aureus. The group aims to understand how such secretion machines work, to elucidate the molecular functions of secreted effector proteins and to explore these insights for therapeutic purpose. To do this, the lab combines structural (cryo-EM, X-ray crystallography) with biochemical and microbiological methods. The group was first to resolve the molecular architecture of the mycobacterial T7SS and provided first insights into the mechanisms of substrate recognition, assembly and bacterial killing by the T7SSb from S. aureus.
In 2022 he was appointed an Associate Professor at the Leiden Institute of Chemistry. At Leiden University his research will focus on understanding mechanisms of microbial virulence with focus on host pathogen communication in tuberculosis.