Amyloid Flashcards
when were first cases of amyloidogenic diseases identifed?
1679
name the 5 types of amyloidogenic diseases?
systemic
hereditary
CNS
ocular
localised
what are systemic conditions?
deposition of amyloid throughout the body
Name as many hereditary fibril proteins that lead to familial systemic amyldosis?
- fibrinogen alpha chain
- apolipoprotein AI
- apolipoprotein AII
- Lysozyme
name as many CNS amyloidogenic diseases ?
- alzheimers
- familial dementia (british - ABri and danish - ADan)
- hereditary cerebral hemorrhage with amyloidosis (icelandic )
name the classes of amyloid diseases
primary
secondary
familial
other types
what is used to identify amyloid deposits?
congo-red
birefringence
how can we determine the location of amyloid deposits in the body?
using 123I-SAP scintigraphy
what is the composition of amyloidogenic deposits?
- fibres (one protein)
- proteoglycans (heparan sulphate, dermatan sulphate, glycosaminoglycans)
- collagen
- serum amyloid P component (SAP)
what methods can we use to solve the structure of amyloid fibrils?
- EM (over fibril morphology)
- Atomic Force Microscopy (over fibril morphology)
- Circular Dichroism (secondary structure)
- fluorescence (fibril assembly)
- fibre diffraction (repeat structures in fibre)
- solid state nmr (local structure/ overall folds)
what does EM show about amyloidogenic deposits?
Fibril morphology
- long thin fibres
- composed of a number of protofilaments
- typically helical
Protofilaments
- vary in width depending on proteins
- repeats along length
X-ray diffraction of amyloid fibrils showed what?
Meridional reflections indicate a regular spacing of 4.8A
Equatorial reflections indicate a spacing between 10-11A
what did x-ray diffraction discover?
That amyloidogenic protein posses B-sheets
- they have same structure as usually found
- seperation between strands corresponds to Pauling structure 4.8A
- The sheets tend not to twist as much as those found in globular proteins
- have to pack side chains
describe the amyloid cross beta structure
5-12A along - variable depending on sidechain packing between sheets
4.8A between - spacing is regular and fixed by H-bonding between beta strands
what four things have scientists noticed about in amyloid deposits
- no evidence for a common sequence
- proteins tend to be hydrophobic (exception is PolyQ in htt -huntingdons)
- slight preference for beta-strands
- minimum size 6 residues
what is anfinsen experiment?
for small globular proteins, native structure (primary structure) is determined only by the protein’s amino acid sequence
what is levinthals paradox?
the amount of time to correctly fold the average protein would exceed the length of time that existed in the universe
what is the process of folding where proteins slowly increase number of favourable interactions to see the lowest energy conformation?
1) possible starting configuration
2) compact configurations
3) transition states
4) native states
because over 30% of the cells volume is occupied by macromolecules how does that effect the protein?
molecular crowding causes a reduced space that a protein can fold in leading to :
- increase in deltaG
- reduction in configurational entropy
- shown to increase the rate of protein aggregation
what part of the extracellular enviroment can affect molecular crowding?
extracellular enviroment rich in glycoaminoglycans, proteoglycans and collagen all demand large volumes
give some examples of where amyloid fibres are found in nature and used
Spidroin - Spiders - to form silk fibres of the web
Curlin - ecoli - to colonise inert surfaces and mediate binding to host proteins
what is beta-2-micro-globulin
makes up the light chain in antigen presentation and its role is quality control
what happens to patients suffering dialysis related amyloidosis?
- once MHC I complex has run its life, dissociation of Betamicroglobulin occurs
- this is released into the blood where it gets degraded in the proximal tubule of the kidney
- people with renal failure normally have an increase in beta levels in blood
- deposition of amyloid fibril in joints (however we are unsure how increased blood levels lead to this)
where is DRA primarily found?
deposits in carpal tunnel
