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MBC in Press, published online ahead of print November 24, 2004
Mol. Biol. Cell 10.1091/mbc.E04-08-0685

A more recent version of this article appeared on February 1, 2005
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Submitted on August 10, 2004
Revised on October 29, 2004
Accepted on November 10, 2004

Munc18-1 Regulates Early and Late Stages of Exocytosis via Syntaxin-independent Protein Interactions

Leonora F. Ciufo,* Jeff W. Barclay,* Robert D. Burgoyne, and Alan Morgan{dagger}

The Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool L69 3BX, United Kingdom

Monitoring Editor: Keith Mostov

Sec1/Munc18 (SM) proteins are involved in various intracellular membrane trafficking steps. Many SM proteins bind to appropriate syntaxin homologues involved in these steps, suggesting that SM proteins function as syntaxin chaperones. Organisms with mutations in SM genes, however, exhibit defects in either early (docking) or late (fusion) stages of exocytosis, implying that SM proteins may have multiple functions. To gain insight into the role of SM proteins, we introduced mutations modeled on those identified in C. elegans, D. melanogaste, and S. cerevisiae into mammalian Munc18-1. As expected, several mutants exhibited reduced binding to syntaxin1A. However, 3 mutants displayed wild-type syntaxin binding affinities, indicating syntaxin-independent defects. Expression of these mutants in chromaffin cells either increased the rate and extent of exocytosis or altered the kinetics of individual release events. This latter effect was associated with a reduced Mint binding affinity in one mutant, implying a potential mechanism for the observed alteration in release kinetics. Furthermore, this phenotype persisted when the mutation was combined with a second mutation that greatly reduced syntaxin binding affinity. These results clarify the data on the function of SM proteins in mutant organisms, and indicate that Munc18-1 controls multiple stages of exocytosis via both syntaxin-dependent and -independent protein interactions.

*These authors contributed equally to this work.

{dagger}Corresponding author. E-mail: amorgan{at}liverpool.ac.uk




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