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Molecular basis of disease > Amyloid > Flashcards

Amyloid Flashcards

1
Q

when were first cases of amyloidogenic diseases identifed?

A

1679

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2
Q

name the 5 types of amyloidogenic diseases?

A

systemic
hereditary
CNS
ocular
localised

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3
Q

what are systemic conditions?

A

deposition of amyloid throughout the body

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4
Q

Name as many hereditary fibril proteins that lead to familial systemic amyldosis?

A
  • fibrinogen alpha chain
  • apolipoprotein AI
  • apolipoprotein AII
  • Lysozyme
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5
Q

name as many CNS amyloidogenic diseases ?

A
  • alzheimers
  • familial dementia (british - ABri and danish - ADan)
  • hereditary cerebral hemorrhage with amyloidosis (icelandic )
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6
Q

name the classes of amyloid diseases

A

primary
secondary
familial
other types

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7
Q

what is used to identify amyloid deposits?

A

congo-red
birefringence

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8
Q

how can we determine the location of amyloid deposits in the body?

A

using 123I-SAP scintigraphy

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9
Q

what is the composition of amyloidogenic deposits?

A
  • fibres (one protein)
  • proteoglycans (heparan sulphate, dermatan sulphate, glycosaminoglycans)
  • collagen
  • serum amyloid P component (SAP)
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10
Q

what methods can we use to solve the structure of amyloid fibrils?

A
  • 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)
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11
Q

what does EM show about amyloidogenic deposits?

A

Fibril morphology
- long thin fibres
- composed of a number of protofilaments
- typically helical

Protofilaments
- vary in width depending on proteins
- repeats along length

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12
Q

X-ray diffraction of amyloid fibrils showed what?

A

Meridional reflections indicate a regular spacing of 4.8A
Equatorial reflections indicate a spacing between 10-11A

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13
Q

what did x-ray diffraction discover?

A

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

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14
Q

describe the amyloid cross beta structure

A

5-12A along - variable depending on sidechain packing between sheets
4.8A between - spacing is regular and fixed by H-bonding between beta strands

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15
Q

what four things have scientists noticed about in amyloid deposits

A
  • 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
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16
Q

what is anfinsen experiment?

A

for small globular proteins, native structure (primary structure) is determined only by the protein’s amino acid sequence

17
Q

what is levinthals paradox?

A

the amount of time to correctly fold the average protein would exceed the length of time that existed in the universe

18
Q

what is the process of folding where proteins slowly increase number of favourable interactions to see the lowest energy conformation?

A

1) possible starting configuration
2) compact configurations
3) transition states
4) native states

19
Q

because over 30% of the cells volume is occupied by macromolecules how does that effect the protein?

A

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

20
Q

what part of the extracellular enviroment can affect molecular crowding?

A

extracellular enviroment rich in glycoaminoglycans, proteoglycans and collagen all demand large volumes

21
Q

give some examples of where amyloid fibres are found in nature and used

A

Spidroin - Spiders - to form silk fibres of the web

Curlin - ecoli - to colonise inert surfaces and mediate binding to host proteins

22
Q

what is beta-2-micro-globulin

A

makes up the light chain in antigen presentation and its role is quality control

23
Q

what happens to patients suffering dialysis related amyloidosis?

A
  • 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)
24
Q

where is DRA primarily found?

A

deposits in carpal tunnel

25
Q

describe structure of soluble Beta two microglobulin

A
  • over 80 X-ray/ NMR structures od b2m in MHC-I
  • seven stranded beta sheet fold typical of Ig superfamily
  • two sheets composed of residues A, B, E, D and C,F,G
  • Disulphide bond C25/C80
  • Strand D is split
26
Q

Name four key components in the structure of Beta-2-micro fibrils

A
  • steric zipper
  • Beta turn
  • pi-stacking
  • Cys bonded leg
27
Q

How can we detect B2m fibril formation?

A

its detected by a change in the emission spectrum of ThioflavinT (ThT)

28
Q

What study was done to test factors controlling fibrillogenesis?

A

Myers et al. 2006
compared ThT fluorescene (therefore fold change of B2m fibril) in the presence of agents found in amyloid deposits such as SAP, Heparin, Collagen etc.
All showed that they synergestically work to cause fold-change

28
Q

What study was done to test factors controlling fibrillogenesis?

A

Myers et al. 2006
compared ThT fluorescene (therefore fold change of B2m fibril) in the presence of agents found in amyloid deposits such as SAP, Heparin, Collagen etc.
All showed that they synergestically work to cause fold-change

29
Q

what happens when there is a deletion of the six N-terminal residues?

A

allows B2m to spontaneously form fibrils

30
Q

how could you destabilise B2m?

A

deletion of the N-6 terminal residues

31
Q

Name three facts about b2m when there is an N terminal deletion of 6 residues?

A
  • in-vivo deposits contain >25% (od B2M with 6 deletion)
  • folded structure is 2.5kcalmol-1 less stable
  • has a greater propensity to oligomerise in solution (size exclusion chromatography)
32
Q

what destabilises B2m protein structure in-vivo?

A
  • Cu2+
  • Lysolipids
  • Truncated protein
  • Advanced glycation end products (AGE)
33
Q

what stabilises B2m protein structure in-vivo and what else can they do?

A

they act as template for aggregation
- heparin (GAGs)
- Collagen
- SAP

34
Q

what destabilises B2m protein in-vitro?

A
  • detergents
  • acidic conditions
  • Ionic strength
  • TFE

Molecular basis of disease (5 decks)

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