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Journal Article

Syntaxin1a variants lacking an N-peptide or bearing the LE mutation bind to Munc18a in a closed conformation.

MPS-Authors
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Burkhardt,  P.
Research Group of Structural Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Fasshauer,  D.
Research Group of Structural Biochemistry, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

1835328.pdf
(Publisher version), 616KB

Supplementary Material (public)

1835328_Supplement_I.pdf
(Supplementary material), 729KB

Citation

Colbert, K. N., Hattendorf, D. A., Weiss, T. M., Burkhardt, P., Fasshauer, D., & Weis, W. I. (2013). Syntaxin1a variants lacking an N-peptide or bearing the LE mutation bind to Munc18a in a closed conformation. Proceedings of the National Academy of Sciences of the United States of America, 110(31), 12637-12642. doi:10.1073/pnas.1303753110.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-4CB9-2
Abstract
In neurons, soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins drive the fusion of synaptic vesicles to the plasma membrane through the formation of a four-helix SNARE complex. Members of the Sec1/Munc18 protein family regulate membrane fusion through interactions with the syntaxin family of SNARE proteins. The neuronal protein Munc18a interacts with a closed conformation of the SNARE protein syntaxin1a (Syx1a) and with an assembled SNARE complex containing Syx1a in an open conformation. The N-peptide of Syx1a (amino acids 1-24) has been implicated in the transition of Munc18a-bound Syx1a to Munc18a-bound SNARE complex, but the underlying mechanism is not understood. Here we report the X-ray crystal structures of Munc18a bound to Syx1a with and without its native N-peptide (Syx1a Delta N), along with small-angle X-ray scattering (SAXS) data for Munc18a bound to Syx1a, Syx1a Delta N, and Syx1a L165A/E166A (LE), a mutation thought to render Syx1a in a constitutively open conformation. We show that all three complexes adopt the same global structure, in which Munc18a binds a closed conformation of Syx1a. We also identify a possible structural connection between the Syx1a N-peptide and SNARE domain that might be important for the transition of closed-to-open Syx1a in SNARE complex assembly. Although the role of the N-peptide in Munc18a-mediated SNARE complex assembly remains unclear, our results demonstrate that the N-peptide and LE mutation have no effect on the global conformation of the Munc18a-Syx1a complex.