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J. Biol. Chem., Vol. 282, Issue 16, 12097-12103, April 20, 2007

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Functionally and Spatially Distinct Modes of munc18-Syntaxin 1 Interaction^*

Colin Rickman, Claire N. Medine, Axel Bergmann, and Rory R. Duncan¹

From the Centre for Integrative Physiology, University of Edinburgh, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom and Becker & Hickl GmbH, Nahmitzer Damm 30, 12277 Berlin, Germany

Eukaryotic membrane trafficking is a conserved process under tight temporal and spatial regulation in which the fusion of membranes is driven by the formation of the ternary SNARE complex. Syntaxin 1a, a core component of the exocytic SNARE complex in neurons and neuroendocrine cells, is regulated directly by munc18-1, its cognate Sec1p/munc18 (SM) protein. SM proteins show remarkable structural conservation throughout evolution, indicating a common binding mechanism and function. However, SM proteins possess disparate binding mechanisms and regulatory effects with munc18-1, the major brain isoform, classed as atypical in both its binding specificity and its mode. We now show that munc18-1 interacts with syntaxin 1a through two mechanistically distinct modes of binding, both in vitro and in living cells, in contrast to current models. Furthermore, these functionally divergent interactions occur at distinct cellular locations. These findings provide a molecular explanation for the multiple, spatially distinct roles of munc18-1.

Received for publication, January 9, 2007 , and in revised form, January 30, 2007.

^* This work was funded by a Wellcome Trust Fellowship award (to R. R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-131-6502864; Fax: 44-131-6503128; E-mail: rory.duncan{at}ed.ac.uk.

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