Journal: J Mol Biol / Year: 2019 Title: The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease. Authors: Ana-Caroline Raulin / Lucas Kraft / Youssra K Al-Hilaly / Wei-Feng Xue / John E McGeehan / John R Atack / Louise Serpell / Abstract: Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late- ...Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late-onset Alzheimer's disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158, and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerization state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small-angle x-ray scattering, analytical ultracentrifugation, circular dichroism, x-ray fiber diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerize to form wavy filaments, which do not share the characteristics of cross-β amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis, and these results open opportunities for uncovering new triggers for AD onset.
Instrument name: Diamond Light Source B21 / City: Oxfordshire / 国: UK / Shape: 1 x 5 mm / Type of source: X-ray synchrotron / Wavelength: 0.1 Å / Dist. spec. to detc.: 3.9 mm
Detector
Name: Pilatus 2M
Scan
Title: Apolipoprotein E2 / Measurement date: Nov 29, 2017 / Storage temperature: 4 °C / Cell temperature: 20 °C / Exposure time: 3 sec. / Number of frames: 7 / Unit: 1/A /
Min
Max
Q
0.0034
0.3696
Distance distribution function P(R)
Sofotware P(R): GNOM 4.6 / Number of points: 367 /
Min
Max
Q
0.008942
0.2513
P(R) point
23
389
R
0
194.5
Result
Type of curve: sec Comments: Sample concentration: UNKNOWN. The experimental molecular weight (MW) quoted in this entry (144 kDa) was determined using multi-angle laser light scattering (MALLS). Analytical ...Comments: Sample concentration: UNKNOWN. The experimental molecular weight (MW) quoted in this entry (144 kDa) was determined using multi-angle laser light scattering (MALLS). Analytical ultracentrifugation provides a MW estimate of 122 kDa.
Experimental
Porod
MW
144 kDa
-
Volume
-
400 nm3
P(R)
Guinier
Guinier error
Forward scattering, I0
0.2785
0.276
0.00049
Radius of gyration, Rg
5.82 nm
5.634 nm
0.063
Min
Max
D
-
19.45
Guinier point
22
89
+
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