Molecular mechanism of secreted amyloid-β precursor protein in binding and modulating GABABR1a

Mei Feng, Yi Song, Serena H. Chen, Yuanzhao Zhang, Ruhong Zhou

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

A recent phenomenal study discovered that the extension domain of secreted amyloid-β precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a) and modulate its synaptic transmission. The work provided an important structural foundation for the modulation of GABABR1a; however, the detailed molecular interaction mechanism, crucial for future drug design, remains elusive. Here, we further investigated the dynamical interactions between sAPP peptides and the natively unstructured sushi 1 domain using all-atom molecular dynamics simulations, for both the 17-residue sAPP peptide (APP 17-mer) and its minimally active 9 residue segment (APP 9-mer). We then explored mutations of the APP 9-mer with rigorous free energy perturbation (FEP) calculations. Our in silico mutagenesis studies revealed key residues (D4, W6, and W7) responsible for the binding with the sushi 1 domain. More importantly, one double mutation based on different vertebrate APP sequences from evolution exhibited a stronger binding (ΔΔG = -1.91 ± 0.66 kcal mol-1), indicating a potentially enhanced GABABR1a modulator. These large-scale simulations may provide new insights into the binding mechanism between sAPP and the sushi 1 domain, which could open new avenues in the development of future GABABR1a-specific therapeutics.

Original languageEnglish
Pages (from-to)6107-6116
Number of pages10
JournalChemical Science
Volume12
Issue number17
DOIs
StatePublished - May 7 2021

Funding

We would like to thank Prof. Joris De Wit for sending us the NMR structure of APP 9-mer bound with sushi-1 domain (PDB coordinates). We also thank Wei Song, David Bell, Binquan Luan, and Zonglin Gu for help with the manuscript. This work is partially supported by the National Natural Science Foundation of China (grants U1967217 and 11574224) and China Postdoctoral Science Foundation (grant 2019M652052). R. Z. also acknowledges the nancial support from W. M. Keck Foundation (grant award 2019-2022) and National Independent Innovation Demonstration Zone Shanghai Zhangjiang Major Projects (ZJZX2020014).

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