{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Granados AJ"],"funding":["NIGMS NIH HHS","NIH HHS"],"pubmed_abstract":["Norrin is an atypical ligand that regulates retinal angiogenesis through the Wnt/β-catenin pathway by triggering heterodimerization of Frizzled-4 (FZD4) with Low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to downstream β-catenin stabilization. Unlike Wnt ligands, Norrin requires the tetraspanin Tspan12 for signaling amplification, but it is not understood why. Here, we report a 3.4-angstrom structure of Tspan12 in complex with FZD4 determined by cryo-electron microscopy. The structure reveals that FZD4 and Tspan12 form a direct complex in the absence of Norrin, with a contact interface between the lower hinge of FZD4 and the extracellular loops of Tspan12 that enables FZD4 to respond with a more gradual response to a wider range of Norrin concentrations. The tran"],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2025.09.25.678640"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12485846"],"repository":["biostudies-literature"],"pubmed_title":["Structural basis for regulation of Frizzled-4 signaling by the co-receptor Tetraspanin-12."],"pmcid":["PMC12485846"],"funding_grant_id":["DP5 OD036136","R25 GM056847"],"pubmed_authors":["Alamo KAE","Susa KJ","Granados AJ","Pratap PP"],"additional_accession":[]},"is_claimable":false,"name":"Structural basis for regulation of Frizzled-4 signaling by the co-receptor Tetraspanin-12.","description":"Norrin is an atypical ligand that regulates retinal angiogenesis through the Wnt/β-catenin pathway by triggering heterodimerization of Frizzled-4 (FZD4) with Low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to downstream β-catenin stabilization. Unlike Wnt ligands, Norrin requires the tetraspanin Tspan12 for signaling amplification, but it is not understood why. Here, we report a 3.4-angstrom structure of Tspan12 in complex with FZD4 determined by cryo-electron microscopy. The structure reveals that FZD4 and Tspan12 form a direct complex in the absence of Norrin, with a contact interface between the lower hinge of FZD4 and the extracellular loops of Tspan12 that enables FZD4 to respond with a more gradual response to a wider range of Norrin concentrations. The tran","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-05-08T03:16:16.218Z","creation":"2026-05-08T03:10:31.191Z"},"accession":"S-EPMC12485846","cross_references":{"pubmed":["41040411"],"doi":["10.1101/2025.09.25.678640"]}}