There are three main projects in my laboratory. One is on the R2TP chaperone complex, the second one is on the Clp proteolytic system, the third one is on mapping the chaperone interaction network. The three projects deal with the common theme of cellular stress response. We are also interested in developing compounds that target protein homeostasis and that can be used as anticancers or antibacterials.
R2TP chaperone complex
Maintaining protein homeostasis in the cell is mainly accomplished by a family of proteins termed molecular chaperones that assist in protein folding. My group identified a highly conserved protein complex, which we named the R2TP complex, that interacts with several other chaperones and adaptor proteins. R2TP consists of the proteins RUVBL1, RUVBL2, RPAP3, and PIH1D1. R2TP acts as a scaffold for the assembly of other critical complexes in the cell. Hence, R2TP has a novel cellular activity dedicated to protein assembly. The aim of the project is to determine the structure and mechanism of function of this complex using cell biological, biochemical, and structural approaches. We are also interested in identifying compounds that inhibit this complex. Hence, the project sheds further insights into the role of chaperones in general and R2TP in particular in cancer.
Our work on the Clp system provided important insights into the function of this chaperone-protease system, especially as regards to its structure and dynamics. Our work concentrates on ClpXP from E. coli, Neisseria, and human. ClpX is a hexameric ATP-dependent unfoldase chaperone, while ClpP is a serine protease that forms a cylindrical tetradecamer with narrow axial pores for substrate entry. In the ClpXP complex, ClpX binds target substrates, unfolds them and threads them into ClpP for degradation. We discovered that the mechanism of release of degradation products from the cylindrical protease ClpP is through the formation of transient equatorial side pores that allow for peptide egress. We also discovered compounds that dysregulate ClpP and that have antibacterial activity. Hence, our research in this field sheds novel insights into bacterial infectivity. We are also interested in understanding the function of the ClpXP system in different other organisms.
Mapping chaperone interaction networks
Molecular chaperones are essential components of a quality control machinery present in the cell. They can either aid in the folding and maintenance of newly translated proteins or they can lead to the degradation of misfolded and destabilized proteins. They are also known to be involved in many cellular functions, however, a detailed and comprehensive overview of the interactions between chaperones and their cofactors and substrates is still absent. The heat shock proteins Hsp90, Hsp70/Hsp40, CCT, and Hsp60/Hsp10 are typical chaperone systems that are highly conserved across organisms. In this project, we are carrying out systematic mapping of the chaperone interaction networks using a wide range of proteomic and genomic methods. The ultimate goal of the project is to determine the mechanisms that govern protein homeostasis inside the cell.