Amyloid Disease Flashcards
what is required in vivo for protein folding
enzymes, chaperones and energy input
what are the possible states of equilibrium between folded, unfolded, misfiled and aggregated
folded-unfoled, misfolded-unfolded, aggregated-unfolded
what does the energy landscape of protein folding look like
rough containing troughs
what sort of proteins sometimes aggregate from an unfolded conformation to form amyloid fibres
intrinsically disordered proteins which are proteins that are functional without adopting a tertiary structure (e.g. transcription factors)
what are the 2 categories of protein misfolding disease
1) they are identified by proteasome leading to degradation and loss of function
2) they are allowed to aggregate leading to loss of function but also gain of toxic function
what happens to misfolded proteins in the ER
they are tagged for degradation and go down the ERAD pathway
what happens to misfolded proteins in the cytosol
they are ubiquitinated and degraded
give 2 examples of diseases caused by errors in the degradation system
Tay-Sachs and Gauchers
how many diseases are associated with amyloid
> 50
what is the structure of amyloid fibrils
they are long thin and unbranched. generic cross beta structure on protofilaments, b strands are organised perpendicular to the finer. many protofilaments form a fibril which is always around 10nm in diameter
give an example of amyloid-like fibres which are good
melanin used to store secretory hormones in vesicles
where to amyloid fibres localise in transthyretin amyloidosis
the heart
where do amyloid fibres localise in systemic amyloidosis
liver
what are the common features of all amyloid fibres
x ray diffraction pattern always gives a 4.8a repeat due to inter strand repeat and 10.7a repeat between cross linking strands
red birefringence
all grow by nucleated growth- monomers form oligomers which then undergo conformational change to form nucleus. at this point many monomers can add quickly- highly structured and ordered
in what ways are amyloid fibres highly polymorphic
can have different numbers of protofilaments, form in different ways
what are the main mutations which occur in lysozyme and why are each of these amyloidogenic
I56T and D67H because they cause misfiling and aggregation
what is the difference between WT lysosyme and mutant lysosyme
variants are less stable and more aggregation prone. in HX ESI MS variant entire b domain concurrently exchange hydrogen atoms en masse
why are camelid antibodies used to prevent lysozyme aggregation rather than human
they bind tightly and specifically like human antibodies but only contain the heavy chain so can be recumbently reproduced more easily
why is it possible to use antibodies to treat amyloid diseases despite them being unable to enter cells
most amyloid diseases are extracellular
how does camelid antibody stabilise mutant lysozyme
it binds the native state and pulls the ab towards the stabilised native state. it also clamps the a and b domains together stopping non-cooperative dissociation and exchange of beta sheet domain which leads to the amyloid precursor
what sort of mutation (gain or loss of function) is tranthyretin amyloidosis
gain of toxic function
where can transthyretin amyloidosis deposit
heart or neurones
what is the disease caused by transthyretin (TTR) amyloidosis deposits in the heart
senile systemic amyloidosis
what is the disease caused by transthyretin amyloidosis deposits in the
familial amyloid polyneuropathy
