title: Synaptotagmin I's Intrinsically Disordered Region Interacts with Synaptic Vesicle Lipids and Exerts Allosteric Control over C2A.
abstract: Synaptotagmin I (Syt I) is a vesicle-localized integral membrane protein that senses the calcium ion (Ca(2+)) influx to trigger fast synchronous release of neurotransmitter. How the cytosolic domains of Syt I allosterically communicate to propagate the Ca(2+) binding signal throughout the protein is not well understood. In particular, it is unclear whether the intrinsically disordered region (IDR) between Syt I's transmembrane helix and first C2 domain (C2A) plays an important role in allosteric modulation of Ca(2+) binding. Moreover, the structural propensity of this IDR with respect to membrane lipid composition is unknown. Using differential scanning and isothermal titration calorimetry, we found that inclusion of the IDR does indeed allosterically modulate Ca(2+) binding within the first C2 domain. Additionally through application of nuclear magnetic resonance, we found that Syt I's IDR interacts with membranes whose lipid composition mimics that of a synaptic vesicle. These findings not only indicate that Syt I's IDR plays a role in regulating Syt I's Ca(2+) sensing but also indicate the IDR is exquisitely sensitive to the underlying membrane lipids. The latter observation suggests the IDR is a key route for communication of lipid organization to the adjacent C2 domains.
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.|Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Fealey
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Mahling
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Rice
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Dunleavy
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: Stephanie E G
authors.initials: SE
authors.lastname: Kobany
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: K Jean
authors.initials: KJ
authors.lastname: Lohese
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Horn
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.|Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Hinderliter
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D000072417:Protein Domains; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism*; D050863:Synaptotagmin I / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008055:Lipids; C494310:SYT1 protein, human; D050863:Synaptotagmin I; D002118:Calcium