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SUMMARY:A tangled problem: the structure\,function and folding of knotted 
 proteins - Jackson\, S (University of Cambridge)
DTSTART:20120904T073000Z
DTEND:20120904T081000Z
UID:TALK39518@talks.cam.ac.uk
CONTACT:Mustapha Amrani
DESCRIPTION:Since 2000\, when they were first identified by Willie Taylor\
 , the number of knotted proteins within the pdb has increased and there ar
 e now nearly 300 such structures. The polypeptide chain of these proteins 
 forms a topologically knotted structure. There are now examples of protein
 s which form simple 31 trefoil knots\, 41\, 52 Gordian knots and 61 Steved
 ore knots. Knotted proteins represent a significant challenge to both the 
 experimental and computational protein folding communities. When and how t
 he polypeptide chain knots during the folding of the protein poses an addi
 tional complexity to the folding landscape. We have been studying the stru
 cture\, folding and function of two types of knotted proteins  the 31-tref
 oil knotted methyltransferases and 52-knotted ubiquitin C-terminal hydrola
 ses. The first part of the talk will focus on our folding studies on knott
 ed trefoil methyltransferases and will include our work on (i) equilibrium
  unfolding experiments in chemical denaturants\, (ii) kinetic analysis of 
 unfolding/folding pathways\, (iii) protein engineering on both the small s
 cale (single point mutants) and large scale (creating N- and C-terminal fu
 sions with a stable beta-grasp domain which are the deepest knotted struct
 ures known)\, (iv) circularisation experiments which establish that the po
 lypeptide chain remains knotted even in the chemically denatured state\, a
 nd (v) recent in vitro translation work which shows that knotting is rate 
 limiting and also shows how GroEL/GroES play a role in the folding of thes
 e proteins in vivo. The second part of the talk will focus on our studies 
 of knotted ubiquitin C-terminal hydrolases  UCH-L1 and UCH-L3. This will i
 nclude equilibrium and kinetic unfolding and folding studies as well as re
 cent work on the effect of point mutants associated with Parkinsons Diseas
 e on the structure\, folding and dynamics of UCH-L1. Recent work on the ef
 fect of oxidative damage on the structure of UCH-L1 will also be described
  and evidence that this protein adopts a partially unfolded form (PUF) on 
 modification with the reactive aldehyde and by-product of cellular oxidati
 ve stress\, HNE\, will be presented. The possible cellular effects of this
  PUF will be discussed. \n
LOCATION:Seminar Room 1\, Newton Institute
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