Journal
CELL REPORTS
Volume 34, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108611
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Funding
- National Natural Science Foundation of China [91854117, 31871425]
- Natural Science Foundation of Jiangsu Province [BK20200036]
- National Institutes of Health (NIH) [GM126960, DK124431, AG061829]
- American Diabetes Association Basic Science Award
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The study demonstrates that SNAREs become fully active when the v-SNARE is split into two fragments, eliminating the need for SM protein activation. Mechanistically, v-SNARE splitting accelerates the zippering of trans-SNARE complexes, mimicking the stimulatory function of SM proteins. SNAREs have the potential to drive efficient membrane fusion but are suppressed by a conformational constraint.
Intracellular vesicle fusion is catalyzed by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Vesicle-anchored v-SNAREs pair with target membrane-associated t-SNAREs to form trans-SNARE complexes, releasing free energy to drive membrane fusion. However, trans- SNARE complexes are unable to assemble efficiently unless activated by Sec1/Munc18 (SM) proteins. Here, we demonstrate that SNAREs become fully active when the v-SNARE is split into two fragments, eliminating the requirement of SM protein activation. Mechanistically, v-SNARE splitting accelerates the zippering of trans-SNARE complexes, mimicking the stimulatory function of SM proteins. Thus, SNAREs possess the full potential to drive efficient membrane fusion but are suppressed by a conformational constraint. This constraint is removed by SM protein activation or v-SNARE splitting. We suggest that ancestral SNAREs originally evolved to be fully active in the absence of SM proteins. Later, a conformational constraint co-evolved with SM proteins to achieve the vesicle fusion specificity demanded by complex endomembrane systems.
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