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Edited by Axel T. Brunger, Stanford University, Stanford, CA, and approved October 15, 2019 (received for review August 12, 2019)
Significance
Although each intracellular fusion event is catalyzed by similar proteins, organelle-specific fusion is essential for accurate protein compartmentation. Prior studies have suggested that specificity resides in the SNARE proteins or in SNAREs and their Sec1/Munc18 (SM) chaperones. The current work, with combinations of SM proteins, R-SNAREs, and Q-SNAREs from yeast vacuole homotypic fusion and from endoplasmic reticulum/cis-Golgi fusion, finds that some noncognate combinations support fusion. However, in the presence of the SNARE disassembly chaperones Sec17/α-SNAP and Sec18/NSF, fusion only occurs when the R-SNARE, Q-SNAREs, and SM protein are derived from the same organelle.
Abstract
Membrane fusion at each organelle requires conserved proteins: Rab-GTPases, effector tethering complexes, Sec1/Munc18 (SM)-family SNARE chaperones, SNAREs of the R, Qa, Qb, and Qc families, and the Sec17/α-SNAP and ATP-dependent Sec18/NSF SNARE chaperone system. The basis of organelle-specific fusion, which is essential for accurate protein compartmentation, has been elusive. Rab family GTPases, SM proteins, and R- and Q-SNAREs may contribute to this specificity. We now report that the fusion supported by SNAREs alone is both inefficient and promiscuous with respect to organelle identity and to stimulation by SM family proteins or complexes. SNARE-only fusion is abolished by the disassembly chaperones Sec17 and Sec18. Efficient fusion in the presence of Sec17 and Sec18 requires a tripartite match between the organellar identities of the R-SNARE, the Q-SNAREs, and the SM protein or complex. The functions of Sec17 and Sec18 are not simply negative regulation; they stimulate fusion with either vacuolar SNAREs and their SM protein complex HOPS or endoplasmic reticulum/cis-Golgi SNAREs and their SM protein Sly1. The fusion complex of each organelle is assembled from its own functionally matching pieces to engage Sec17/Sec18 for fusion stimulation rather than inhibition.
Footnotes
- ↵1To whom correspondence may be addressed. Email: junys{at}gist.ac.kr or Bill.Wickner{at}Dartmouth.edu.
Author contributions: Y.J. and W.W. designed research, performed research, contributed new reagents/analytic tools, analyzed data, and wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1913985116/-/DCSupplemental.
Published under the PNAS license.
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Sec17 (α-SNAP) and Sec18 (NSF) restrict membrane fusion to R-SNAREs, Q-SNAREs, and SM proteins from identical compartments
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