A deep understanding of ttie physiology and biophysics of fusion - and its disease relevance - requires a broad and comprehensive approach and relies heavily upon interdisciplinary approaches honed from a decade of studies of the mechanism of viral envelope fusion. These technologies - cell and molecular biology, surface force/adhesion biophysics, and optical imaging.
The specific aims ofthe initial application covered four aspects of SNARE induced fusion: 1) SNARE distribution, mobility, and lateral interactions within the plane ofthe membrane. 2) Adhesive and molecular forces between SNAREs - determinants of transition states and the energetic. 3) Penultimate states of SNARE fusion: capturing the SNAREpin just before lipid-mixing, with a specific focus on the interplay between lipid structure and protein assembly. 4) Protein and lipidic determinants of fusion kinetics and pore formation.
This broad and comprehensive approach to elucidating the mechanism of intracellular membrane fusion by SNARE proteins will deepen our understanding ofthe physiology and biophysics effusion - and its key roles in diabetes.
| Bello, Oscar D; Jouannot, Ouardane; Chaudhuri, Arunima et al. (2018) Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis. Proc Natl Acad Sci U S A 115:E7624-E7631 |
| Rothman, James E; Krishnakumar, Shyam S; Grushin, Kirill et al. (2017) Hypothesis - buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission. FEBS Lett 591:3459-3480 |
| Wang, Jing; Li, Feng; Bello, Oscar D et al. (2017) Circular oligomerization is an intrinsic property of synaptotagmin. Elife 6: |
| Li, Feng; Tiwari, Neeraj; Rothman, James E et al. (2016) Kinetic barriers to SNAREpin assembly in the regulation of membrane docking/priming and fusion. Proc Natl Acad Sci U S A 113:10536-41 |
| Xu, Weiming; Nathwani, Bhavik; Lin, Chenxiang et al. (2016) A Programmable DNA Origami Platform to Organize SNAREs for Membrane Fusion. J Am Chem Soc 138:4439-47 |
| Bello, Oscar D; Auclair, Sarah M; Rothman, James E et al. (2016) Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores. Langmuir 32:3015-23 |
| Xu, Weiming; Wang, Jing; Rothman, James E et al. (2015) Accelerating SNARE-Mediated Membrane Fusion by DNA-Lipid Tethers. Angew Chem Int Ed Engl 54:14388-92 |
| Zorman, Sylvain; Rebane, Aleksander A; Ma, Lu et al. (2014) Common intermediates and kinetics, but different energetics, in the assembly of SNARE proteins. Elife 3:e03348 |
| Li, Feng; Kümmel, Daniel; Coleman, Jeff et al. (2014) A half-zippered SNARE complex represents a functional intermediate in membrane fusion. J Am Chem Soc 136:3456-64 |
| Shi, Lei; Howan, Kevin; Shen, Qing-Tao et al. (2013) Preparation and characterization of SNARE-containing nanodiscs and direct study of cargo release through fusion pores. Nat Protoc 8:935-48 |
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