Structural basis of calcium-dependent C1ql/BAI assemblies in synaptic connectivity

Structural basis of calcium-dependent C1ql/BAI assemblies in synaptic connectivity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Structural basis of calcium-dependent C1ql/BAI assemblies in synaptic connectivity Zhiyi Wei, Liangyu Liao, Ying Han, Fengfeng Niu, Yingjie Wang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6014540/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Dec, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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 explored C1ql-mediated synaptic connectivity, focusing on the assembly of C1ql1 and its post-synaptic receptor brain-specific angiogenesis inhibitor 3 (BAI3). 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, creating a scaffold that effectively accumulates BAI3 receptors on the plasma membrane. Our cellular and in vivo studies consolidate the essential role of 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. Biological sciences/Biochemistry/Structural biology Biological sciences/Neuroscience/Development of the nervous system/Synaptic development Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 10 Dec, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6014540","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":419251733,"identity":"a5da77a3-5220-4181-a4a9-8c0d6154afcb","order_by":0,"name":"Zhiyi 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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 explored C1ql-mediated synaptic connectivity, focusing on the assembly of C1ql1 and its post-synaptic receptor brain-specific angiogenesis inhibitor 3 (BAI3). 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, creating a scaffold that effectively accumulates BAI3 receptors on the plasma membrane. 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