Homology with vesicle fusion mediator syntaxin-1a predicts determinants of epimorphin/syntaxin-2 function inmammary epithelial morphogenesis

Connie S. Chen, Celeste M. Nelson, Davitte Khauv, Simone Bennett, Evette S. Radisky, Yohei Hirai, Mina J. Bissell, Derek C. Radisky

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

We have shown that branching morphogenesis of mammary ductal structures requires the action of the morphogen epimorphin/syntaxin-2. Epimorphin, originally identified as an extracellular molecule, is identical to syntaxin-2, an intracellular molecule that is a member of the extensively investigated syntaxin family of proteins that mediate vesicle trafficking. We show here that, although epimorphin/syntaxin-2 is highly homologous to syntaxin-1a, only epimorphin/syntaxin-2 can stimulate mammary branching morphogenesis. We construct a homology model of epimorphin/syntaxin-2 based on the published structure of syntaxin-1a, and we use this model to identify the structural motif responsible for the morphogenic activity. We identify four residues located within the cleft between helices B and C that differ between syntaxin-1a and epimorphin/syntaxin-2; through site-directed mutagenesis of these four amino acids, we confer the properties of epimorphin for cell adhesion, gene activation, and branching morphogenesis onto the inactive syntaxin-1a template. These results provide a dramatic demonstration of the use of structural information about one molecule to define a functional motif of a second molecule that is related at the sequence level but highly divergent functionally.

Original languageEnglish (US)
Pages (from-to)6877-6884
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number11
DOIs
StatePublished - Mar 13 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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