Professor Patrick Van der Wel – Studies of amyloid fibrils by solid state NMR

Patrick Van der Wel - seminarMy former colleague, Patrick Van der Wel, visited Berkeley and delivered a seminar, “Investigating amyloid formation mechanisms by studying fibrils by solid-state NMR.” Patrick is a professor in the Department of Structural Biology at the University of Pittsburgh, where he has established a research program that applies solid state NMR to difficult structural targets including insoluble aggregates or proteins within or associated with membranes. An abstract of his presentation and some references follow.

Aggregation of proteins into plaques or amyloid fibrils occurs in a variety of human diseases, including Alzheimer’s, Huntington’s Disease (HD) and prion diseases. Despite intense interest, much remains unknown about the underlying molecular causes – making rational design of treatment strategies difficult. One of the key challenges relates to the fact that the atomic structures of fibrils as well as their precursors are very difficult to characterize. I will discuss our efforts using solid-state NMR to characterize amyloid-like fibrils related to HD and other amyloid-related diseases. We study such fibrils by magic-angle-spinning (MAS) NMR in order to characterize structural features of the fibrils. This involves the detection of local conformation based on site-specific chemical shifts, measurement of distances within and between protein monomers, as well as torsion angle constraints. We leverage NMR’s sensitivity to dynamics to probe site-specific molecular motion, which reveals surface exposure and other key aspects of the aggregates. Part of the discussion will also focus on the implications of SSNMR-derived fibrillar structure for our understanding of the molecular mechanism of fibril formation and disease toxicity. The role of protein domain swapping and a-helix-a-helix interactions in the aggregation pathway will be examined.


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