Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin

Ya Zhu; Xiaowen Lin; Xin Zong; Shuo Han; Mu Wang; Yuxuan Su; Limin Ma; Xiaojing Chu; Cuiying Yi; Qiang Zhao; Beili Wu

doi:10.1038/s41467-022-29361-x

Structural basis of FPR2 in recognition of Aβ₄₂ and neuroprotection by humanin

Nat Commun. 2022 Apr 1;13(1):1775. doi: 10.1038/s41467-022-29361-x.

Authors

Ya Zhu^#¹, Xiaowen Lin^#^{1

2

3}, Xin Zong^#^{1

3}, Shuo Han^#^{1

2

3}, Mu Wang^{1

4}, Yuxuan Su⁵, Limin Ma¹, Xiaojing Chu¹, Cuiying Yi¹, Qiang Zhao^{6

7

8}, Beili Wu^{9

10

11

12}

Affiliations

¹ CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁵ School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
⁶ CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoq@simm.ac.cn.
⁷ University of Chinese Academy of Sciences, Beijing, China. zhaoq@simm.ac.cn.
⁸ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, CAS, Zhongshan, China. zhaoq@simm.ac.cn.
⁹ CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
¹⁰ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. beiliwu@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
¹² School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.

^# Contributed equally.

Abstract

Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ₄₂ and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ₄₂, implying its involvement in the pathogenesis of Alzheimer's disease (AD). However, the interaction pattern between FPR2 and Aβ₄₂ or humanin remains unknown. Here we report the structures of FPR2 bound to G_i and Aβ₄₂ or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ₄₂ and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.

MeSH terms

Amyloid beta-Peptides
Intracellular Signaling Peptides and Proteins
Neuroprotection*
Receptors, Formyl Peptide / chemistry*
Receptors, Formyl Peptide / metabolism
Receptors, Lipoxin / chemistry*

Substances

Amyloid beta-Peptides
FPR2 protein, human
Intracellular Signaling Peptides and Proteins
Receptors, Formyl Peptide
Receptors, Lipoxin
humanin