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Synaptotagmin 1 (Syt 1) is an integral membrane protein responsible for sensing the calcium ion (Ca2+) influx in neurons that triggers synaptic vesicle exocytosis. How Syt 1's intrinsically disordered region (IDR), a ∼60 residue sequence located between the protein's transmembrane helix and two Ca2+-sensing C2 domains, contributes to protein function is not well understood. The same is true of analogous IDRs located in the other synaptotagmin isoforms. Recently, we found that the Syt 1 IDR is structurally responsive to vesicles whose lipid composition mimics that of a synaptic vesicle organelle and that this sensitivity allosterically influences binding and folding behavior of the adjacent C2 domain. We believe these observations may be applicable to the study of other synaptotagmin isoforms and discuss generally how an IDR-membrane interaction could contribute to modulation of C2 domain function.