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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

Cryo-EM and NMR Reveal a Membrane-Gated Doc2B-Munc13-1 Complex and a Helical Doc2B-SNARE-Binding Interface.

  • Cyrus T Rastegar1,2,3
  • Julia Powell1
  • Aleksandra Wosztyl1,2,3
  • Guillaume David1,2,3
  • Klaudia Jaczynska1,2,3
  • Xiao-Chen Bai1
  • Yan Han1
  • Zhe Chen1
  • Josep Rizo1,2,3
  1. 1Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  2. 2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  3. 3Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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Abstract

Doc2s modulate neurotransmitter release through interactions with Munc13-1, SNAREs, lipids, and Ca²⁺, which involve the Doc2 C₂ domains and Munc13-interacting domain (MID). However, it is unclear how these interactions are coupled, how Doc2s bind to Munc13-1, and how they bind to the SNAREs. Here we determined the cryo-electron microscopy structure of a Doc2B-Munc13-1 complex aided by an AI-designed Munc13-1 binder, revealing how Doc2B MID binds to a Munc13-1 hydrophobic pocket essential for opening syntaxin-1 and explaining why Doc2B inhibits SNARE assembly. NMR and fluorescence spectroscopy show that Doc2B MID binds lipids and that MID-lipid and MID-Munc13-1 interactions are mutually exclusive, suggesting that membrane binding helps release the inhibition of Munc13-1. NMR shows that Doc2B binds to the SNARE complex via two helices of C₂B. Based on these results and liposome fusion assays, we propose a working model whereby: 1. Doc2B MID-Munc13-1 interactions facilitate synergistic binding of both proteins to the plasma membrane, with the MID inhibiting Munc13-1. 2. Membrane binding facilitates MID-lipid interactions that transiently relieve the inhibition of Munc13-1, allowing SNARE complex assembly. 3. Doc2B binding to the SNARE complex inhibits neurotransmitter release but generates a primed state that mediates neurotransmitter release by an as-yet-unknown mechanism.

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Cite

BibTeXRIS
BibTeX
@article{rastegar2026cryoem,
  title = {{Cryo-EM and NMR Reveal a Membrane-Gated Doc2B-Munc13-1 Complex and a Helical Doc2B-SNARE-Binding Interface.}},
  author = {Cyrus T Rastegar and Julia Powell and Aleksandra Wosztyl and Guillaume David and Klaudia Jaczynska and Xiao-Chen Bai and Yan Han and Zhe Chen and Josep Rizo},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = nov,
  doi = {10.1002/advs.78011},
  url = {https://europepmc.org/article/MED/42973246},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cryo-EM and NMR Reveal a Membrane-Gated Doc2B-Munc13-1 Complex and a Helical Doc2B-SNARE-Binding Interface.
AU  - Cyrus T Rastegar
AU  - Julia Powell
AU  - Aleksandra Wosztyl
AU  - Guillaume David
AU  - Klaudia Jaczynska
AU  - Xiao-Chen Bai
AU  - Yan Han
AU  - Zhe Chen
AU  - Josep Rizo
PY  - 2026
DA  - 2026/11/03
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78011
UR  - https://europepmc.org/article/MED/42973246
AB  - Doc2s modulate neurotransmitter release through interactions with Munc13-1, SNAREs, lipids, and Ca²⁺, which involve the Doc2 C₂ domains and Munc13-interacting domain (MID). However, it is unclear how these interactions are coupled, how Doc2s bind to Munc13-1, and how they bind to the SNAREs. Here we determined the cryo-electron microscopy structure of a Doc2B-Munc13-1 complex aided by an AI-designed Munc13-1 binder, revealing how Doc2B MID binds to a Munc13-1 hydrophobic pocket essential for opening syntaxin-1 and explaining why Doc2B inhibits SNARE assembly. NMR and fluorescence spectroscopy show that Doc2B MID binds lipids and that MID-lipid and MID-Munc13-1 interactions are mutually exclusive, suggesting that membrane binding helps release the inhibition of Munc13-1. NMR shows that Doc2B binds to the SNARE complex via two helices of C₂B. Based on these results and liposome fusion assays, we propose a working model whereby: 1. Doc2B MID-Munc13-1 interactions facilitate synergistic binding of both proteins to the plasma membrane, with the MID inhibiting Munc13-1. 2. Membrane binding facilitates MID-lipid interactions that transiently relieve the inhibition of Munc13-1, allowing SNARE complex assembly. 3. Doc2B binding to the SNARE complex inhibits neurotransmitter release but generates a primed state that mediates neurotransmitter release by an as-yet-unknown mechanism.
SN  - 2198-3844
ER  -