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SUMMARY:Structural Studies of Alzheimer’s Disease Amyloid Precursor Prot
 ein Dimers
DTSTART;VALUE=DATE-TIME:20141121T010500Z
DTEND;VALUE=DATE-TIME:20141121T012500Z
DTSTAMP;VALUE=DATE-TIME:20260811T073139Z
UID:indico-contribution-764@events01.synchrotron.org.au
DESCRIPTION:Speakers: Chen Gao (Structural Biology Laboratory and ACRF Rat
 ional Drug Discovery Centre\, St Vincent's Institute of Medical Research\,
  University of Melbourne\, Melbourne\, Vic\, Australia)\nAmyloid precursor
  protein (APP) is a type-I transmembrane protein with a large ectodomain (
 sAPP)\, a single transmembrane domain and a cytoplasmic tail. It is cleave
 d by beta- and gamma-secretases to generate amyloid-β (Aβ)\, a neurotoxi
 c peptide implicated in Alzheimer’s disease (AD). APP dimerisation is cl
 osely linked to Aβ overproduction. It is also implicated in APP signallin
 g as APP is proposed to be membrane receptor. There are four potential dim
 erisation sites in APP\, three of which are located in the sAPP region. Ho
 wever\, the mechanism of APP dimerisation remains unclear. Understanding A
 PP dimerisation mechanisms at the molecular level will not only provide in
 sights into how APP signals but also have therapeutic implications. Severa
 l factors are found to regulate APP proteolysis in vivo. To test their imp
 act on sAPP dimerisation\, we used in vitro techniques including ThermoFlu
 or\, analytical ultracentrifugation and multi-angle light scattering. We f
 ound certain metals and sugars synergistically drive sAPP dimerisation\, w
 hich is associated with conformational changes and increased stability. Th
 is discovery has led to the successful crystallisation of sAPP in its dime
 ric forms. The identities of metal ions were confirmed using anomalous dif
 ference Fourier maps. Key features underlying sAPP dimer formation are cle
 arly demonstrated in the structure. Together with results from the solutio
 n studies\, the crystal structure has provided a leap forward in understan
 ding the mechanism of APP dimerisation and its pathogenic and functional i
 mplications. The structure will be used to discover inhibitors of APP dime
 risation and Aβ overproduction as possible AD therapeutics.\n\nhttps://ev
 ents01.synchrotron.org.au/event/3/contributions/764/
LOCATION: Oliphant Auditorium
URL:https://events01.synchrotron.org.au/event/3/contributions/764/
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