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Experimental studies on the folding pathways of knotted proteins

Banff International Research Station for Mathematical Innovation and Discovery

Since 2000, when they were first identified by Willie Taylor, the number of knotted proteins within the pdb has increased and there are now nearly 300 such structures. The polypeptide chain of these proteins forms a topologically knotted structure. There are now examples of proteins which form simple 3_1 trefoil knots, 4_1, 5_2 Gordian knots and 6_1 Stevedore knots. Knotted proteins represent a significant challenge to both the experimental and computational protein folding communities. When and how the polypeptide chain knots during the folding of the protein poses an additional complexity to the folding landscape. We have been studying the structure, folding and function of two types of knotted proteins – the 3_1 -trefoil knotted methyltransferases and 5_2 -knotted ubiquitin C- terminal hydrolases. The first part of the talk will focus on our folding studies on knotted trefoil methyltransferases and will include our work determining the kinetic pathways by which such proteins fold, protein engineering studies which have created the deepest knotted protein structures known, experimental evidence for the retention of knots even in highly unstructured denatured polypeptide chains. In addition, recent work on the effect of molecular chaperones on the folding of these proteins, and new experimental evidence determining whether threading occurs from the N- or C-termini will be discussed. The second part of the talk will focus on our studies of knotted ubiquitin C-terminal hydrolases – UCH-L1 and UCH-L3. Our work determining the folding pathways of these proteins will be presented, including recent unpublished work using NMR techniques to characterise the folding intermediates. The link between UCH-L1 and Parkinson’s Disease will be discussed and the role of point mutations and oxidative damage on the structure of UCH-L1 will also be described.

Mathematics; Biology and other natural sciences; Manifolds and cell complexes; Mathematical biology

video/mp4

Author affiliation: University of Cambridge

2014-08-07

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/49723

Unreviewed

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/