Leukocyte immunoglobulin-like receptor B2 (LilrB2) is one of discovered cell surface β-amyloid (Aβ) receptors and taken as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Aβ42 oligomer rather than monomer is toxic to neuronal cells and can directly bind to LilrB2, resulting in synaptic loss and cognitive impairment in the development of AD. Therefore, uncovering the mechanism of interaction between Aβ42 oligomer and LilrB2 becomes the first step to obtain a clear drug target and specific binding sites. Herein, a tetracoordinated mechanism for the Aβ oligomer-LilrB2 binding was first put forward by employing Aβ42 dimer mimic-antiparallel copies of Aβ42 core fragment 16KLVFFA21, to bind LilrB2 as models, in which four key residues (F5/F6/L12/F14) in the Aβ42 mimic are bound strongly with LilrB2 residue(s) or accommodated by four hydrophobic cavities in LilrB2 to generate a stable complex. Bi-dentate binding, however, cannot keep the complex Aβ42 mimic-LilrB2 stable. The inhibitor fluspirilene can disturb the binding of four key residues of Aβ42 to LilrB2, justifying the tetracoordinated zipper mechanism on the other hand.
Keywords: 16KLVFFA21; Aβ oligomer; Fluspirilene; LilrB2; Tetracoordinated zipper mechanism.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.