Volume 33, No 2, Feb 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 2, February 2023: 116-130

ORIGINAL ARTICLES

LilrB3 is a putative cell surface receptor of APOE4

Jiayao Zhou^1,2,†,* , Yumeng Wang^3,† , Gaoxingyu Huang^1,2 , Min Yang³ , Yumin Zhu⁴ , Chen Jin³ , Dan Jing^1,2 , Kai Ji^1,2 , Yigong Shi^1,2,3,*

¹Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
²Zhejiang Provincial Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
³Advanced Research Center for Biological Structure & Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
⁴Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, Anhui, China
^†These authors contributed equally: Jiayao Zhou, Yumeng Wang
Correspondence: Jiayao Zhou(zhoujiayao@westlake.edu.cn)Yigong Shi(syg@westlake.edu.cn)

The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms.

https://doi.org/10.1038/s41422-022-00759-y

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