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SUMMARY:Regulation of amyloid self-assembly under partially denaturing sol
 ution conditions - Prof Martin Muschol (University of South Florida)
DTSTART:20100610T150000Z
DTEND:20100610T160000Z
UID:TALK23650@talks.cam.ac.uk
CONTACT:Dr Mark Miller
DESCRIPTION:Accumulation of insoluble protein fibrils is a hallmark of mul
 tiple organ-specific and systemic human disorders\, including Alzheimer's 
 disease\, Parkinson's disease and type-II diabetes.  Understanding the mol
 ecular and cellular mechanisms regulating and promoting the formation of s
 uch amyloid fibrils in vitro and in vivo represents a major challenge both
  for basic scientists and health care professionals.\n\nOur laboratory is 
 interested in identifying overarching physical principles regulating the s
 elf-assembly of amyloidogenic proteins into mature fibrils. We've been stu
 dying amyloid formation using the native folded protein hen egg-white lyso
 zyme.  Combining in-situ dynamic light scattering (DLS) with atomic force 
 microscopy (AFM)\, fluorescence and CD-spectroscopy we have investigated h
 ow in-vitro growth conditions affect the nucleation and growth kinetics as
  well as the assembly pathways of amyloid fibril formation under partially
  denaturing conditions.  We found that lysozyme displayed three different 
 growth regimes characterized by distinct nucleation and growth kinetics\, 
 diverse intermediate aggregate species and changes in net protein interact
 ions. At low salt concentrations amyloid self-assembly proceeds via polyme
 rization of monomeric species. As salt concentration increases compact oli
 gomer form which subsequently assemble into larger polymers. Eventually\, 
 ordered fibril assembly transitions into disordered precipitation.  Our da
 ta further suggest that amyloid fibril assembly proceeds under conditions 
 of net protein repulsion which is the opposite to conditions favorable for
  protein crystallization. We will discuss the evidence for the conclusions
  and suggest a simple model to explain both the observed transitions in fi
 bril assembly pathways and the differences in solution conditions promotin
 g fibril formation vs. crystallization.
LOCATION:Unilever Lecture Theatre\, Department of Chemistry
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