Structural insights into the in situ assembly of clustered protocadherin γB4

Ze Zhang, Fabao Chen, Zihan Zhang, Luqiang Guo, Tingting Feng, Zhen Fang, Lihui Xin, Yang Yu, Hongyu Hu, Yingbin Liu and Yongning He ()
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Ze Zhang: Shanghai Jiao Tong University School of Medicine
Fabao Chen: Shanghai Jiao Tong University School of Medicine
Zihan Zhang: Shanghai Jiao Tong University School of Medicine
Luqiang Guo: The University of Texas at Austin
Tingting Feng: Shanghai Jiao Tong University School of Medicine
Zhen Fang: Shanghai Jiao Tong University School of Medicine
Lihui Xin: Chinese Academy of Sciences
Yang Yu: Chinese Academy of Sciences
Hongyu Hu: Chinese Academy of Sciences
Yingbin Liu: Shanghai Jiao Tong University School of Medicine
Yongning He: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Clustered protocadherins (cPcdhs) belong to the cadherin superfamily and play important roles in neural development. cPcdhs mediate homophilic adhesion and lead to self-avoidance and tiling by giving neurons specific identities in vertebrates. Structures and functions of cPcdhs have been studied extensively in past decades, but the mechanisms behind have not been fully understood. Here we investigate the in situ assembly of cPcdh-γB4, a member in the γ subfamily of cPcdhs, by electron tomography and find that the full length cPcdh-γB4 does not show regular organization at the adhesion interfaces. By contrast, cPcdh-γB4 lacking the intracellular domain can generate an ordered zigzag pattern between cells and the cis-interacting mode is different from the crystal packing of the ectodomain. We also identify the residues on the ectodomain that might be important for the zigzag pattern formation by mutagenesis. Furthermore, truncation mutants of the intracellular domain reveal different assembly patterns between cell membranes, suggesting that the intracellular domain plays a crucial role in the intermembrane organization of cPcdh-γB4. Taken together, these results suggest that both ectodomain and intracellular domain regulate the in situ assembly of cPcdh-γB4 for homophilic cell adhesion, thereby providing mechanistic insights into the functional roles of cPcdhs during neuronal wiring.

Date: 2025
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DOI: 10.1038/s41467-025-56948-x

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