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Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion


Malmersjö, Seth; Di Palma, Serena; Diao, Jiajie; Lai, Ying; Pfuetzner, Richard A; Wang, Austin L; McMahon, Moira A; Hayer, Arnold; Porteus, Matthew; Bodenmiller, Bernd; Brunger, Axel T; Meyer, Tobias (2016). Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion. EMBO Journal Online, 35(16):1810-1821.

Abstract

Membrane fusion is essential for eukaryotic life, requiring SNARE proteins to zipper up in an α-helical bundle to pull two membranes together. Here, we show that vesicle fusion can be suppressed by phosphorylation of core conserved residues inside the SNARE domain. We took a proteomics approach using a PKCB knockout mast cell model and found that the key mast cell secretory protein VAMP8 becomes phosphorylated by PKC at multiple residues in the SNARE domain. Our data suggest that VAMP8 phosphorylation reduces vesicle fusion in vitro and suppresses secretion in living cells, allowing vesicles to dock but preventing fusion with the plasma membrane. Markedly, we show that the phosphorylation motif is absent in all eukaryotic neuronal VAMPs, but present in all other VAMPs. Thus, phosphorylation of SNARE domains is a general mechanism to restrict how much cells secrete, opening the door for new therapeutic strategies for suppression of secretion.

Abstract

Membrane fusion is essential for eukaryotic life, requiring SNARE proteins to zipper up in an α-helical bundle to pull two membranes together. Here, we show that vesicle fusion can be suppressed by phosphorylation of core conserved residues inside the SNARE domain. We took a proteomics approach using a PKCB knockout mast cell model and found that the key mast cell secretory protein VAMP8 becomes phosphorylated by PKC at multiple residues in the SNARE domain. Our data suggest that VAMP8 phosphorylation reduces vesicle fusion in vitro and suppresses secretion in living cells, allowing vesicles to dock but preventing fusion with the plasma membrane. Markedly, we show that the phosphorylation motif is absent in all eukaryotic neuronal VAMPs, but present in all other VAMPs. Thus, phosphorylation of SNARE domains is a general mechanism to restrict how much cells secrete, opening the door for new therapeutic strategies for suppression of secretion.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 August 2016
Deposited On:17 Jan 2017 14:19
Last Modified:06 Aug 2017 21:44
Publisher:Nature Publishing Group
ISSN:0261-4189
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/embj.201694071
PubMed ID:27402227

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