The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors

Wei Li; Cong Ma; Rong Guan; Yibin Xu; Diana R Tomchick; Jose Rizo-Rey

doi:10.1016/j.str.2011.07.012

The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors

Wei Li, Cong Ma, Rong Guan, Yibin Xu, Diana R Tomchick, Jose Rizo-Rey

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

Abstract

Unc13/Munc13s play a crucial function in neurotransmitter release through their MUN domain, which mediates the transition from the Syntaxin-1/Munc18-1 complex to the SNARE complex. The MUN domain was suggested to be related to tethering factors, but no MUN-domain structure is available to experimentally validate this notion and address key unresolved questions about the interactions and minimal structural unit required for Unc13/Munc13 function. Here we identify an autonomously folded module within the MUN domain (MUN-CD) and show that its crystal structure is remarkably similar to several tethering factors. We also show that the activity in promoting the Syntaxin-1/Munc18-1 to SNARE complex transition is strongly impaired in MUN-CD. These results show that MUN domains and tethering factors indeed belong to the same family and may have a common role in membrane trafficking. We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences.

Original language	English (US)
Pages (from-to)	1443-1455
Number of pages	13
Journal	Structure
Volume	19
Issue number	10
DOIs	https://doi.org/10.1016/j.str.2011.07.012
State	Published - Oct 12 2011

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/j.str.2011.07.012

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title = "The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors",

abstract = "Unc13/Munc13s play a crucial function in neurotransmitter release through their MUN domain, which mediates the transition from the Syntaxin-1/Munc18-1 complex to the SNARE complex. The MUN domain was suggested to be related to tethering factors, but no MUN-domain structure is available to experimentally validate this notion and address key unresolved questions about the interactions and minimal structural unit required for Unc13/Munc13 function. Here we identify an autonomously folded module within the MUN domain (MUN-CD) and show that its crystal structure is remarkably similar to several tethering factors. We also show that the activity in promoting the Syntaxin-1/Munc18-1 to SNARE complex transition is strongly impaired in MUN-CD. These results show that MUN domains and tethering factors indeed belong to the same family and may have a common role in membrane trafficking. We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences.",

author = "Wei Li and Cong Ma and Rong Guan and Yibin Xu and Tomchick, {Diana R} and Jose Rizo-Rey",

note = "Funding Information: We thank Nan Shen for initial work on crystallization of the MUN domain; Yilun Sun for expert technical assistance; Bingke Yu, Jimin Pei, and Nick Grishin for fruitful discussions; and Zbyszek Otwinowsky for advice on data reduction. The structure shown in this report is derived from work performed on beamlines 19-BM and 19-ID at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This work was supported by a postdoctoral fellowship from the American Heart Association (to Y.X.), by Welch foundation grant I-1304, and by NIH grant NS37200 (to J.R.). ",

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AU - Ma, Cong

AU - Guan, Rong

AU - Xu, Yibin

AU - Tomchick, Diana R

AU - Rizo-Rey, Jose

N1 - Funding Information: We thank Nan Shen for initial work on crystallization of the MUN domain; Yilun Sun for expert technical assistance; Bingke Yu, Jimin Pei, and Nick Grishin for fruitful discussions; and Zbyszek Otwinowsky for advice on data reduction. The structure shown in this report is derived from work performed on beamlines 19-BM and 19-ID at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This work was supported by a postdoctoral fellowship from the American Heart Association (to Y.X.), by Welch foundation grant I-1304, and by NIH grant NS37200 (to J.R.).

PY - 2011/10/12

Y1 - 2011/10/12

N2 - Unc13/Munc13s play a crucial function in neurotransmitter release through their MUN domain, which mediates the transition from the Syntaxin-1/Munc18-1 complex to the SNARE complex. The MUN domain was suggested to be related to tethering factors, but no MUN-domain structure is available to experimentally validate this notion and address key unresolved questions about the interactions and minimal structural unit required for Unc13/Munc13 function. Here we identify an autonomously folded module within the MUN domain (MUN-CD) and show that its crystal structure is remarkably similar to several tethering factors. We also show that the activity in promoting the Syntaxin-1/Munc18-1 to SNARE complex transition is strongly impaired in MUN-CD. These results show that MUN domains and tethering factors indeed belong to the same family and may have a common role in membrane trafficking. We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences.

AB - Unc13/Munc13s play a crucial function in neurotransmitter release through their MUN domain, which mediates the transition from the Syntaxin-1/Munc18-1 complex to the SNARE complex. The MUN domain was suggested to be related to tethering factors, but no MUN-domain structure is available to experimentally validate this notion and address key unresolved questions about the interactions and minimal structural unit required for Unc13/Munc13 function. Here we identify an autonomously folded module within the MUN domain (MUN-CD) and show that its crystal structure is remarkably similar to several tethering factors. We also show that the activity in promoting the Syntaxin-1/Munc18-1 to SNARE complex transition is strongly impaired in MUN-CD. These results show that MUN domains and tethering factors indeed belong to the same family and may have a common role in membrane trafficking. We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences.

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The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors

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