Journal
ELIFE
Volume 6, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.27000
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Funding
- Danish Medical Research Council
- European Research Council [ERC-ADG-322966-DCVfusion]
- Lundbeckfonden
- Novo Nordisk Foundation
- University of Copenhagen [2016 (KU2016)]
- Lundbeck Foundation [R28-2008-1976, R34-2009-3740, R221-2016-1202, R183-2014-3274] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0021198, NNF14OC0012557] Funding Source: researchfish
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Doc2B is a cytosolic protein with binding sites for Munc13 and Tctex-1 (dynein light chain), and two C2-domains that bind to phospholipids, Ca2+ and SNAREs. Whether Doc2B functions as a calcium sensor akin to synaptotagmins, or in other calcium-independent or calcium-dependent capacities is debated. We here show by mutation and overexpression that Doc2B plays distinct roles in two sequential priming steps in mouse adrenal chromaffin cells. Mutating Ca2+-coordinating aspartates in the C2A-domain localizes Doc2B permanently at the plasma membrane, and renders an upstream priming step Ca2+-independent, whereas a separate function in downstream priming depends on SNARE-binding, Ca2+-binding to the C2B-domain of Doc2B, interaction with ubMunc13-2 and the presence of synaptotagmin-1. Another function of Doc2B - inhibition of release during sustained calcium elevations - depends on an overlapping protein domain (the MID-domain), but is separate from its Ca2+-dependent priming function. We conclude that Doc2B acts as a vesicle priming protein.
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