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Biography

Rivka obtained a B.Sc. in Biochemistry from the University of Manchester in 1997 followed by a Ph.D. in Chemistry from the University of Cambridge in 2001 under the supervision of Professor Sir Alan Fersht, FRS. She carried out post-doctoral research at Harvard Medical School with Professor Pamela Silver and then at Imperial College London with Professor Steve Matthews. Subsequently, she worked at the Imperial College Drug Discovery Centre before starting her own research group in 2009 funded by an MRC New Investigator Research Grant.

Research Interests

 

The Isaacson group uses biophysical techniques, with a focus on NMR spectroscopy, to determine macromolecular structure and interactions of molecules relevant to health and disease.

Quality Control at the Endoplasmic Reticulum

In the crowded environment of the cell, quality control mechanisms are vital. Proteins that are obsolete or have strayed from their operative environments must be recycled or rehoused. When hydrophobic proteins are, for any reason, exposed to the cytosol they are rapidly captured by protective complexes which shield them from the aqueous surroundings and decide their fate (by either targeting them to their correct membrane homes or marking them for degradation by the ubiquitin/proteasome system). The BAG6 holdase is a heterotrimeric protein complex, comprising BAG6, UBL4a and TRC35, which works closely with the cochaperone SGTA to triage hydrophobic proteins and pass them along the appropriate pathway. SGTA also interacts with viral proteins and hormone receptors and is upregulated in numerous cancer types. These functions require further investigation to determine the scope of SGTA as a therapeutic target.

Our lab has solved the solution structure of the N-terminal dimerization domain of SGTA and characterised its interaction with two different ubiquitin-like (UBL) domains in the BAG6 holdase (one from UBL4A and the other from BAG6 itself) using NMR chemical shift perturbation data and other biophysical techniques including ITC and MST. We continue to structurally characterise further key players that participate in this quality control, with the aim of clarifying the intricate network of molecular interactions that governs these processes in health and disease.This work is performed in collaboration with Professor Stephen High at the University of Manchester and is funded by BBSRC grant BB/L006952/1 ‘The structure and function of SGTA, a key regulator of protein quality control’ which runs until mid-2017.

Bacterial Gene Regulation

Both prokaryotic and eukaryotic cells can completely change their phenotypes by synchronising the shut-down of one gene expression programme with the activation of another. These highly choreographed events occur in numerous aspects of biology and are crucial for health and disease. In B. subtilis sporulation a gene expression switch occurs in which the forespore shuts off its sigma factor F (SigF) driven programme of transcription to activate the genes controlled by sigma factor G (SigG). This switch is regulated by various mechanisms including a vital role for SigG inhibitor, Gin, and its more recently discovered SigF inhibitor relative, Fin, a conserved sporulation protein about which little is so far known. Effecting this switch requires precise mechanisms to keep the new gene expression array in check until the old one is deactivated and, by extrapolation, mechanisms to maintain repression of the old programme once the new one is in play. Our work employs a wide range of biophysical techniques to determine the molecular mechanisms of this important gene expression switch event. Our results inform in vivo mutagenesis studies in B. subtilis by our collaborators at Mt Holyoke (Prof. Amy Camp) and Harvard (Prof. Rich Losick), which, in turn, feed back into our work to probe this mechanism in atomic level detail. With the ongoing problem of 'hospital superbugs' this detailed exploration of sporulation has the long-term potential to identify entirely novel approaches to therapeutic intervention and the development of new antibiotics. 

Dr Rivka Isaacson Research Portal