Misfolding Flashcards
What SNP increases the likelihood of genetic TSEs?
valine to methionine in regions of structure that mutate.
polymorphisms at residue 129
Amyloidosis - what mutationn destabilised lysozyme?
Loss of H bond at position 67 and 56.
Give an example of a possible therapy for FAP.
Stabilise tetramer - incorporate T199M into V30M disease subunits –> increases activation energy for tetramer dissociation.
OR Tafamidis - structural complementarity to T4 binding sites but not a thyroid agonist / antagonist - binds T4 binding sites which stabilises tetramer.
What structures does misfolded Sup35 form?
Crystal structure shows infinite B-sheet array.
Describe the collision of malformed PrPc
Collision with another protein has enough energy to induce misfolding and then polymerisation –> infinite arrays of B-sheets at RIGHT angles to fibre axis.
What exactly is an amyloid?
lateral assembly of PROTEIN AGGREGATES adopting a cross-B structure. (bind congo red. thioflavin T)
What experiment suggested that ability to form amyloids may be a common property of peptides?
Acylphosphatase not associated with any disease & is soluble.
Add trifluoroethanol (denatures proteins where H bonds between peptide groups still STABLE)
Protein formed amyloid fibrils.
As intermolecular bonds stabilising amyloid fibrils are involved in peptide backbone common to all proteins may be a common property.
Describe the fibril structure of TTR.
Protofilaments built up from 4 continuous twisted B-sheets of indefinite length running parallel to axis fibril with strands running perpendicular.
4 B-sheets arranged in pairs - each stabilised by hypho core between two sheets.
What is the NACore?
residues 68-78 (11 residues) responsible for amyloid formation and cytoxicity of a-synuclein. Determined to 1.4 A resolution by micro electron diffraction.
