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SUMMARY:Beta-hairpin motifs of amyloidogenic IDPs - Dr Wolfgang Hoyer\, In
 stitute of Physical Biology\, University of Dusseldorf
DTSTART:20161026T093000Z
DTEND:20161026T103000Z
UID:TALK68758@talks.cam.ac.uk
CONTACT:Priyanka Joshi
DESCRIPTION:The conformational ensembles of intrinsically disordered prote
 ins (IDPs) contain substantial fractions of conformers that exhibit long-r
 ange intramolecular interactions. We have investigated beta-hairpin motifs
  of islet amyloid polypeptide (IAPP)\, alpha-synuclein\, and amyloid-beta 
 peptide (Abeta). Applying NMR spectroscopy\, we have identified a beta-hai
 rpin conformation of IAPP in complex with an engineered binding protein\, 
 the beta-wrapin HI18. The beta-strands of the IAPP beta-hairpin correspond
  to two amyloidogenic sequence motifs which are connected by a turn establ
 ished around Ser-20. Apart from monomers\, HI18 binds oligomers and fibril
 s and inhibits IAPP aggregation and toxicity at low substoichiometric conc
 entrations\, indicating that the IAPP beta-hairpin can serve as a molecula
 r recognition motif enabling control of IAPP aggregation. In a similar vei
 n\, the related beta-wrapin AS10 inhibits amyloid formation\, exhibiting s
 ub-micromolar affinity for each of the three amyloidogenic IDPs IAPP\, alp
 ha-synuclein and Abeta\, demonstrating that multi-specific monomer-binding
  agents can be generated. In the case of alpha-synuclein\, we have identif
 ied a beta-hairpin formed in the sequence region 35-59 which contains the 
 beta-strand segments b1 and b2 of amyloid fibril models and most disease-r
 elated mutations. We show by disulfide engineering\, biophysical technique
 s\, and cell viability assays\, that intramolecular tertiary interactions 
 between the b1 and b2 segments of alpha-synuclein interfere with its aggre
 gation\, and moreover inhibit aggregation of IAPP and amyloid-beta peptide
 . Our results reveal a common preference of different amyloidogenic protei
 ns for formation of beta-hairpin motifs and demonstrate a critical role of
  hairpin conformers in the control of amyloid formation.
LOCATION:Unilever  Lecture Theatre\,  Department of Chemistry
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