CBC Colloquium Series: "Disordered regions on the surface of amyloid fibrils and their interaction with chaperones"

Presenter:  

Dr. Ansgar Siemer

Associate Professor of Physiology & Neuroscience

Keck School of Medicine, USC

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Abstract: 

Thanks to cryo-electron microscopy and solid-state NMR, we now know the cross-β core structures of most amyloid fibrils responsible for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. However, many amyloid fibrils include extensive intrinsically disordered regions (IDRs) besides their cross-β cores. These IDRs often constitute the majority of the fibril surface and are key epitopes of fibril-specific binders.

From an NMR point of view, these IDRs are neither strictly solid nor in solution creating unique challenges for obtaining good NMR data. Therefore, we are exploring different NMR techniques to access these regions of intermediate dynamics. In addition, we combine NMR with CW and DEER EPR data and MD simulation with the goal of creating fibril models that includes both the static amyloid core and the IDRs.

In a next step, we are studying the interaction of proteins with amyloid IDRs. Specifically, we are interested in the binding of the co-chaperone DNAJB1 to the IDRs found in α-synuclein and huntingtin exon-1 fibrils. DNAJB1 is the initial binder of a trimeric chaperone complex, together with Hsc70 and APG2, which can disaggregate amyloid fibrils. We showed that DNAJB1 binds the C-terminal IDRs in both cases and found that post-translational modifications result in increased DNAJB1 binding. 

Bio:

The aim of my laboratory is to create a better understanding of the pathological and functional aspects of protein disorder and aggregation. In particular, I am interested in how the proteins and other biomolecules such as chaperones interact with the surface of amyloid fibrils and their precursors thereby modulating toxicity or function. Already as an undergraduate, I worked on aspects of protein misfolding. During my PhD and postdoctoral training, I learned and applied solid-state NMR spectroscopy to determine the structure and dynamics of various amyloid fibrils. I established my lab at USC in 2012 where we started using many other biophysical techniques besides solid-state NMR. The main projects over the last decade have been the exon-1 of huntingtin (HTTex1) important in Huntington’s disease (HD), Orb2, a functional amyloid important in long-term memory, and α-synuclein important in Parkinson’s Disease (PD). The work on HTTex1 and α-synuclein has shifted my interest towards the intrinsically disordered regions (IDR) that frequently frame the static core of amyloid fibrils and towards understanding how chaperones such as DNAJB1, DNAJB6, and DNAJB8 interact with fibrils and fibril precursors. For example in our most recent publication (d), we used solid-state NMR in combination with MD simulations to show how DNAJB1 binds to α-synuclein fibrils.

Hosted by: Dr. Marielle Hegetschweiler/Walti