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SUMMARY:Special LMNN seminar - Prion Protein Biology Through the Lens of L
 iquid-Liquid Phase Separation: A Tale of an Intrinsically Disordered Tail
DTSTART:20220701T150000
DTEND:20220701T160000
DTSTAMP:20260428T021501Z
UID:e3c89aff4e34c57b5e24a11e987e8cfa8efc07c30ef688e80d638a11
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Samrat Mukhopadhyay\, Indian Institute of Science Educa
 tion and Research (IISER) Mohali\n \nLiquid-liquid phase separation (LLPS
 ) of intrinsically disordered proteins/regions (IDPs/IDRs) into intracellu
 lar biomolecular condensates is involved in critical cellular functions. H
 owever\, aberrant phase transitions are associated with debilitating neuro
 degenerative diseases. We show that the prion protein (PrP) can undergo LL
 PS via weak\, multivalent\, transient intermolecular interactions between 
 the N-terminal IDR that resembles a yeast prion-like domain comprising fiv
 e glycine-rich octapeptide repeats and a hydrophobic segment. An intriguin
 g disease-associated amber stop codon mutation (Y145Stop) yields a C-termi
 nally truncated intrinsically disordered fragment that is associated with 
 Gerstmann-Sträussler-Scheinker syndrome and familial cerebral amyloid ang
 iopathy. We demonstrate that Y145Stop spontaneously phase-separates into h
 ighly dynamic liquid droplets under physiological conditions. Our bioinfor
 matic\, spectroscopic\, microscopic\, and mutational studies coupled with 
 single-droplet vibrational Raman spectroscopy revealed highly dynamic inte
 rnal organization within condensates and illuminated the critical molecula
 r drivers of LLPS of Y145Stop. We also show that Y145Stop exhibits a reent
 rant phase behavior in the presence of RNA. Upon aging\, these highly dyna
 mic liquid droplets undergo a liquid-to-solid phase transition into highly
  ordered\, beta-rich\, amyloid aggregates that exhibit a characteristic au
 tocatalytic self-templating behavior. Therefore\, LLPS-mediated amyloid fo
 rmation can potentially represent a noncanonical phase transition pathway 
 to self-replicating prions. The propensity for this aberrant phase transit
 ion is much lower for the full-length PrP indicating an evolutionarily con
 served role of the folded C-terminal domain. I will also discuss our recen
 t results on spatiotemporal modulation in complex coacervation of PrP and 
 alpha-synuclein into multicomponent\, multiphasic\, hollow condensates. Th
 ese multicomponent condensates can act as reaction crucibles to catalyze t
 he amyloid conversion of these functional assemblies into pathological agg
 regates associated with overlapping neuropathological features. I will al
 so discuss our latest work on the characterization of biomolecular condens
 ates using ultrasensitive vibrational Raman spectroscopy.\n\n 
LOCATION:AI 1153 https://plan.epfl.ch/?room==AI%201153 https://epfl.zoom.u
 s/j/65270545422
STATUS:CONFIRMED
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