Based on the discovery of the inherent capacity of SNARES to fuse membranes, now demonstrated for mammalian exocytic, yeast ER- Golgi, and yeast vacuolar SNARES, the overall goal of the proposed research is to test directly and comprehensively whether SNARE-dependent fusion is a general principle in biology (aims 1- 6) and the extent to which compartmental specificity is encoded in SNARE proteins (aim 7). We will capitalize on the completion of the yeast genome to enable these fundamental questions for cell biology to be addressed in a single cell type which will also be extensively harnessed to provide critical genetic tests of the physiological relevance of the findings from biochemistry (aim 8). It is now within our reach to completely characterize the binding interactions and fusogenic capacity of every SNARE protein in the yeast cell, and this is indeed our intent. The process of vesicular transport is of basic importance to biology and medicine, underlying the compartmental organization of the cytoplasm and the pathways of exocrine, endocrine, and neurosecretion. Knowledge of the mechanism of action of gene products in these pathways, and their allelic variants, will likely be important for predictive medicine and impact upon management of common diseases such as cancer, diabetes, cardiovascular disease and diseases of the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027044-26
Application #
6634868
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Haft, Carol R
Project Start
1991-09-30
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
26
Fiscal Year
2003
Total Cost
$593,123
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Rebane, Aleksander A; Wang, Bigeng; Ma, Lu et al. (2018) Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly. J Mol Biol 430:479-490
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
Wu, Zhenyong; Bello, Oscar D; Thiyagarajan, Sathish et al. (2017) Dilation of fusion pores by crowding of SNARE proteins. Elife 6:
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
Wang, Yong Jian; Li, Feng; Rodriguez, Nicolas et al. (2016) Snapshot of sequential SNARE assembling states between membranes shows that N-terminal transient assembly initializes fusion. Proc Natl Acad Sci U S A 113:3533-8
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
Wu, Zhenyong; Auclair, Sarah M; Bello, Oscar et al. (2016) Nanodisc-cell fusion: control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domains. Sci Rep 6:27287

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