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Publication Abstract from PubMed

Cell adhesion molecules (CAMs) are pivotal in establishing and maintaining synaptic connectivity. Emerging evidence indicates that some secreted factors within the synaptic cleft, including C1q-like proteins (C1qls), play a crucial role in bridging pre- and post-synapses by connecting the bilateral CAMs. However, the mechanisms of those secreted factors in synapse assembly remain incomplete. Here, we explore C1ql-mediated synaptic connectivity, focusing on the assembly of C1ql1 and its postsynaptic receptor brain-specific angiogenesis inhibitor 3 (BAI3, also called ADGRB3). Our biochemical, structural, and computational analyses reveal that the trimeric globular C1q (gC1q) domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer. Cryo-EM study manifests the stabilizing role of calcium ions on the C1ql1_gC1q hexamer in complex with the extended CUB domain of BAI3. Using the gC1q hexamer, full-length C1ql1 further assembles into linear clusters, possibly providing a scaffold to accumulate BAI3 receptors on the plasma membrane. Our cellular and in vivo studies support a role for the gC1q-mediated dynamic assembly of C1ql1 in receptor accumulation and synapse maintenance. Collectively, our findings provide a plausible mechanism of secreted factor-mediated synaptic connectivity, driven by the calcium-modulated assembly of C1qls and their interactions with CAMs.

Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity.,Liao L, Han Y, Niu F, Wang Y, Lu Y, Xu S, Zhu H, Lin L, Xiao J, Tou HI, Gao J, Zhang B, Wei Z Nat Commun. 2025 Dec 10. doi: 10.1038/s41467-025-66254-1. PMID:41372137^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.