Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity
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Abstract
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.
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- Authors
- Liao, L., Han, Y., Niu, F., Wang, Y., Lu, Y., Xu, S., Zhu, H., Lin, L., Xiao, J., Tou, H. I., Gao, J., Zhang, B., & Wei, Z.
- Affiliations
- Southern University of Science and Technology (CN)
- Peking University (CN)
- Shenzhen Bay Laboratory (CN)
- University of Minnesota (US)
- Corresponding author
- Zhang, Bo
- Wei, Zhiyi
- ORCID
- Venue
- Nature Communications
- Published
- 2025-12-10
- Volume
- 16
- Issue
- 1
- Pages
- 11444-11444
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12749725
- OpenAlex
- W4417184825
- Cited by
- 4
- References
- 5
- Citations by year
- 2026: 4
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (32471250)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- C1QL1, BAI3, synaptic connectivity, adhesion molecules, CUB domain, synapse maintenance, synaptic cleft
- MeSH terms
- Protein Domains, Animals, Calcium, Humans, Nerve Tissue Proteins, Synapses, Cryoelectron Microscopy, Mice, HEK293 Cells
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