Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E

Abstract

Among various isoforms of Apolipoprotein E (ApoE), the E4 isoform (ApoE4) is considered to be the strongest risk factor for Alzheimer's disease, whereas the E3 isoform (ApoE3) is neutral to the disease. Interestingly, the sequence of ApoE4 differs from its wild-type ApoE3 by a single amino acid C112R in the 299-amino-acid-long sequence. Hence, the puzzle remains: how a single-amino-acid difference between the ApoE3 and ApoE4 sequences can give rise to structural dissimilarities between the two isoforms, which can potentially lead to functional differences with significant pathological consequences. The major obstacle in addressing this question has been the lack of a 3D atomistic structure of ApoE4 to date. In this work, we resolve the issue by computationally modeling a plausible atomistic 3D structure of ApoE4. Our microsecond-long atomistic simulations elucidate key structural differences between monomeric ApoE3 and ApoE4, which renders ApoE4 thermodynamically less stable, less structured, and topologically less rigid compared to ApoE3. Consistent with an experimental report of the molten globule state of ApoE4, simulations identify multiple partially folded intermediates for ApoE4, which are implicated in the stronger aggregation propensity of ApoE4.

Association between APOE polymorphisms and lipid profile in Mexican Amerindian population

“…The three ApoE isoforms are originated from the substitution of these amino acid residues and lead to differential functions in lipid metabolism (Boerwinkle, Brown, Sharrett, Heiss, & Patsch, ; Boerwinkle & Utermann, ; Gregg & Brewer, ; Gregg et al, ; Hauser, Narayanaswami, & Ryan, ; Villeneuve, Brisson, & Gaudet, ). Additionally, each isoform of ApoE conveys a different risk of some diseases, such as Alzheimer's disease (AD) (Chen, Baum, Ng, Chan, & Pang, ) schizophrenia (Vila‐Rodriguez, Honer, Innis, Wellington, & Beasley, ), osteoporosis (Singh, Singh, Singh, Juneja, & Kaur, ), or arteriosclerosis, which could be due the different functions and structures of the ApoE isoforms (Mahley, Weisgraber, & Huang, ; Ray, Ahalawat, & Mondal, ).…”

Apolipoprotein E particle size is increased in Alzheimer's disease

“…The linker between the NH 2 and CO 2 H-terminal domains becomes less protease-sensitive on lipid binding. Molecular modeling studies have shown [9] that apoE4 is topologically less rigid than apoE3 and can exist in a "molten globule" state.…”

Domino-like Effect of C112R Mutation on ApoE4 Aggregation and Its Reduction by Alzheimer’s Disease Drug Candidate

“…This structural interpretation is further supported by computer simulations, which showed destabilization and bending of the H3 helix in APOE4. Altered intradomain interaction and H3 bending as a consequence of C112R substitution and R61 rearrangement in APOE4 have been previously reported [60][61][62] . These conformational changes make APOE4 more susceptible to chemical and thermal denaturation than APOE3 and APOE2 63,64 .…”