biostudies-literatureTao MNINDS NIH HHSNational Institutes of HealthNIGMS NIH HHS5301https://www.ebi.ac.uk/biostudies/studies/S-EPMC7093510biostudies-literatureUnknown10(1)Membrane protein oligomerization mediates a wide range of biological events including signal transduction, viral infection and membrane curvature induction. However, the relative contributions of protein-protein and protein-membrane interactions to protein oligomerization remain poorly understood. Here, we used the Ca²⁺-dependent membrane-binding protein ANXB12 as a model system to determine the relative contributions of protein-protein and protein-membrane interactions toward trimer formation. Using an EPR-based detection method, we find that some protein-protein interactions are essential for trimer formation. Surprisingly, these interactions are largely hydrophobic, and they do not include the previously identified salt bridges, which are less important. Interfering with membScientific reportsAnnexin B12 Trimer Formation is Governed by a Network of Protein-Protein and Protein-Lipid Interactions.PMC7093510R01 NS084345R01NS084345R01 GM115736Tao MIsas JMLangen RfalseAnnexin B12 Trimer Formation is Governed by a Network of Protein-Protein and Protein-Lipid Interactions.Membrane protein oligomerization mediates a wide range of biological events including signal transduction, viral infection and membrane curvature induction. However, the relative contributions of protein-protein and protein-membrane interactions to protein oligomerization remain poorly understood. Here, we used the Ca²⁺-dependent membrane-binding protein ANXB12 as a model system to determine the relative contributions of protein-protein and protein-membrane interactions toward trimer formation. Using an EPR-based detection method, we find that some protein-protein interactions are essential for trimer formation. Surprisingly, these interactions are largely hydrophobic, and they do not include the previously identified salt bridges, which are less important. Interfering with memb2020-01-01T00:00:00Z2020 Mar2026-06-07T08:01:56.494Z2025-05-29T21:25:40.136ZS-EPMC70935103221035010.1038/s41598-020-62343-x