Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 33, Issue 5, Pages -Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E21-11-0583
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Funding
- National Institute of General Medical Sciences [R35GM118037]
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Membrane fusion is a complex process involving various proteins, including SNAREs and different families of chaperones. Recent studies have revealed that the physiological juxtamembrane (Jx) regions of R- and Qa-SNAREs are necessary for fusion, and this fusion block can be bypassed by other proteins. Additionally, factors other than the abundance of trans-SNARE complexes can affect the fusion process.
Membrane fusion requires tethers, SNAREs of R, Qa, Qb, and Qc families, and chaperones of the SM, Sec17/SNAP, and Sec18/NSF families. SNAREs have N-domains, SNARE domains that zipper into 4-helical RQaQbQc coiled coils, a short juxtamembrane (Jx) domain, and (often) a C-terminal transmembrane anchor. We reconstitute fusion with purified components from yeast vacuoles, where the HOPS protein combines tethering and SM functions. The vacuolar Rab, lipids, and R-SNARE activate HOPS to bind Q-SNAREs and catalyze trans-SNARE associations. With SNAREs initially disassembled, as they are on the organelle, we now report that R- and Qa-SNAREs require their physiological juxtamembrane (Jx) regions for fusion. Swap of the Jx domain between the R- and Qa-SNAREs blocks fusion after SNARE association in trans. This block is bypassed by either Sec17, which drives fusion without requiring complete SNARE zippering, or transmembrane-anchored Qb-SNARE in complex with Qa. The abundance of the trans-SNARE complex is not the sole fusion determinant, as it is unaltered by Sec17, Jx swap, or the Qb-transmembrane anchor. The sensitivity of fusion to Jx swap in the absence of a Qb transmembrane anchor is inherent to the SNAREs, because it remains when a synthetic tether replaces HOPS.
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