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Apolipoprotein E4 exhibits intermediates with domain interaction.

Subhrajyoti Dolai1, Sreelakshmi Cherakara1, Kanchan Garai1

  • 1Tata Institute of Fundamental Research Hyderabad, 36/P, Gopanpally Village, Serilingampally, Hyderabad 500019, India.

Biochimica Et Biophysica Acta. Proteins and Proteomics
|September 4, 2020
PubMed
Summary
This summary is machine-generated.

Apolipoprotein E4 (ApoE4) is linked to Alzheimer's disease. Substitutions at residue 112 affect its domain interactions, potentially creating intermediate states in ApoE4 that drive disease pathology.

Keywords:
Alzheimer's diseaseApolipoprotein EDomain interactionFree energyMolten globule

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Apolipoprotein E4 (ApoE4) is the primary genetic risk factor for Alzheimer's disease (AD).
  • The C112R substitution in ApoE4 is thought to alter interactions between its N-terminal (NTD) and C-terminal domains (CTD), leading to functional differences compared to normal ApoE3.
  • Understanding these domain interactions is crucial for elucidating ApoE4's role in AD pathogenesis.

Purpose of the Study:

  • To investigate how molecular properties at residue 112 influence apoE's domain interaction.
  • To quantify the free energy of domain interaction (ΔGINT) across various C112X substitutions.
  • To explore the structural basis for ApoE4's increased risk in Alzheimer's disease.

Main Methods:

  • Utilized an array of C112X substitutions (R, A, T, V, L, I) to probe residue effects.
  • Calculated free energy of domain interaction (ΔGINT) using stabilities of full-length and fragmented apoE domains (ΔGNTD, ΔGCTD, ΔGNTF, ΔGCTF).
  • Monitored domain interaction stability via urea-induced changes in interdomain Förster Resonance Energy Transfer (FRET); assessed 'intermediate' states using bis-ANS fluorescence and proteolytic cleavage susceptibility.

Main Results:

  • While N-terminal domain (NTD) stability varied with C112X substitutions, the change in NTD stability (ΔGNTD - ΔGNTF) and C-terminal domain (CTD) stability (ΔGCTD ≈ ΔGCTF) suggested small, similar ΔGINT across isoforms.
  • Interdomain FRET stability, however, showed strong dependence on C112X substitutions, with ApoE4 exhibiting the highest denaturation midpoint.
  • ApoE4, particularly its NTD, demonstrated characteristics of 'intermediate' states in native and mildly denaturing conditions, evidenced by enhanced bis-ANS fluorescence and increased proteolytic susceptibility.

Conclusions:

  • Despite similar calculated free energies of domain interaction, ApoE4 exhibits altered interdomain stability, suggesting a more dynamic or less stable interaction.
  • The presence of 'intermediate' structural states in ApoE4, especially within the NTD, is proposed as a key factor contributing to its pathological functions in Alzheimer's disease.
  • These findings highlight the importance of conformational dynamics and intermediate states in understanding the disease-associated properties of ApoE isoforms.