A key challenge in molecular medicine is to develop cures for diseases for which no cure exists – such as Alzheimer, Parkinson or ALS, but also many other diseases with dramatic impact for the affected individual such as ataxias or cystic fibrosis. These diseases have in common that the molecular cause is related to uncontrolled consequences of protein damage and aggregation. Our body is not unprotected against protein damage. The fidelity of protein shape in the cell is maintained by a powerful proteostasis network, in which molecular chaperones and proteases play a key role. This networks supresses the appearance of most folding related diseases for the best part of our life. However, why does it suddently fail when we get older? Why do some individuals get a protein-aggregation related disease and others do not? Can we boost the cellular defense system to prevent the origin of the disease, or at least prevent progress of the diseases for some cases? My group aims to understand protein folding processes in the cell and their consequence for the origin of fatal diseases. We connect three related research themes:
Role of proteostasis in Alzheimer disease
The cell controls shaping of newly-made proteins and the removal of damaged or problematic proteins. This control is essential for life, derailing of this control is fatal. The most prominent failure is the aggregation of the protein Tau, which ultimately leads to Alzheimer Disease. Resetting control of Tau maintenance would provide a causal therapy for Alzheimer, but at present this fails due to a lack of understanding at molecular level. Molecular chaperones such as the Hsp90 chaperone are the first line of the cellular defense system against protein damage and aggregation. The chaperones are part of the proteostasis network, the natural defense system against protein damage problems. Hsp90 interacts in vivo and in vitro with the Tau protein. We have recently described a structural model of an Hsp90-Tau complex, showing the Tau protein behaves as a bona fide client of the Hsp90 chaperone. We found Hsp90 to bind to the Tau’s microtubule-binding repeat region, which forms the toxic aggregates. Together this suggests a direct role for Hsp90 in dealing with Tau aggregation. We hypothesize that molecular chaperones typically counter aggregation of Tau, but a decrease in chaperoning capacity at higher age may allow fatal aggregation to proceed. Our aim is now to test the function of the natural defense system in the origin of of Alzheimer Disease. We rare currently exploring whether and how molecular chaperones can control aggregation and disaggregation of Alzheimer fibrils.
Protein damage and cancer mutants
Signalling proteins are key clients of the chaperone Hsp90, many of which are membrane-standing signalling proteins. We work on understanding the link between protein quality control and cancer. We analyse the mechanism of action of cancer point mutants in tumour suppressors, using the Wnt signalling cascade as a model. We investigate how cancer point mutations in a key scaffold protein induced tumour growth. In particular, we analyse the hypothesis that mutations may lead to structural destabilisation and subsequent oligomerisation of tumour suppressor proteins. This is important as such changes may affect lead to loss of interaction with crucial binding partners, but it may also form novel, abberrant and potentially toxic interactions. A key aim for us is to understand the interaction of the natural defense against protein damage, the proteostasis network, with nanoaggregates.
Decision making on protein fate in the cell
Hsp70 chaperones act early and Hsp90 late in the folding path, yet the molecular basis of this timing had been enigmatic. We obtained a structural model of Hsp90 in complex with its natural substrate, the intrinsically disordered Tau protein. Our model resolved the paradox on how Hsp90 specifically selects for late folding intermediates but also for some intrinsically disordered proteins – through the eyes of Hsp90 they look the same. It is striking, however, that key details of the active cycle of Hsp90 are known, but the big picture is still enigmatic – what is the actual function of Hsp90 chaperones in the cell? Our work is dedicated to provide an answer to this question. We recenty indentified the molecular mechanism why and how the Hsp70 and Hsp90 form a partnership to fold proteins.
The trademark of our work is answering burning biological questions with an interdiciplinary range of methods, to make use of the wealth of methods offered on the Utrecht campus, from molecule to organism.
We have expertise to prepare complex proteins for biological studies. We characterise them using biochemical assays, such as folding assays or fluorescence methods to analyse protein stability and protein-protein interactions. We use integrated structural biology approaches e.g by combining NMR spectroscopy and SAXS to characterise protein complexes or EM methods to get structural insights into biological processes. We are currently transferring insights obtained by our structural and biochemical studies into living cells.