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SUMMARY:Dynamic chaperone–client-interactions characterized at atomic re
 solution
DTSTART:20190409T164500
DTEND:20190409T180000
DTSTAMP:20260428T163558Z
UID:73ed66a1a723a1b63f2a5ca8b1201d55959a1fa496e71aec4345306c
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Sebastian Hiller (University of Basel)\nMolecular chaper
 ones are essential in cellular protein homeostasis. Central mechanistic as
 pects of chaperone function are not well understood at the atomic level\, 
 including how chaperones recognize clients\, in which conformational state
 s clients are bound\, and how chaperone–client interactions are integrat
 ed into functional cycles. Solution NMR spectroscopy is the only method to
  resolve dynamic chaperone–client interactions at atomic resolution\, gi
 ving us enormous potential to address these questions. Our initial work on
  the homotrimeric holdase chaperone Skp with bound outer membrane proteins
  provided the first atomic-level description of a natural full-length chap
 erone­­–client complex [1\, 2]. Subsequent work showed how periplasmic
  chaperones shape individual client folding trajectories at the membrane b
 ilayer [3]. We now find that the monomeric state of the chaperone Skp is i
 ntrinsically disordered\, and that oligomerization initiates folding via a
  “stapling” mechanism. This coupled oligomerization\, folding and clie
 nt-binding mechanism is a unique mechanistic example of how an ATP-indepen
 dent chaperone can modulate its activity.\nAn atomic-resolution characteri
 zation of the Spy–Im7 model system revealed general principles how Spy a
 nd other chaperones selectively recognize the flexible\, locally frustrate
 d regions of partially folded clients [4\,5]. These mechanistic insights w
 ere fruitfully used to investigate the functional role of chaperones in Pa
 rkinson’s disease. Parkinson’s disease is a common neurodegenerative d
 isorder manifested by intracellular aggregates of the intrinsically disord
 ered protein α-Synuclein. Systematic investigations identified a general 
 chaperone interaction motif at the α-Synuclein amino-terminus. A dominant
  regulatory role of chaperones on cytosolic α-Synuclein was validated wit
 h in-cell NMR spectroscopy and the functional basis for the effects of kno
 wn post-translational modifications could be reconstituted. The data revea
 l how molecular chaperones control the state of intracellular α-Synuclein
  and how the disturbance of these interactions leads to progress of pathol
 ogically relevant aggregates.\n\nWritten by .S. Hiller1\, B. M. Burmann1\,
  G. Mas1\, R. Riek2\, J. A. Gerez2 -\n1Biozentrum\, University of Basel\, 
 4056 Basel\, Switzerland.\n2Laboratory of Physical Chemitrsy\, ETH Zürich
 \, 8093 Zurich\, Switzerland.\n \n 
LOCATION:CH G1 495 https://plan.epfl.ch/?room==CH%20G1%20495
STATUS:CONFIRMED
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