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Physical and Functional Interactions of SNAP-23 with Annexin A2

Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma

Correspondence and requests for reprints should be addressed to Lin Liu, Ph D., Department of Physiological Sciences, Oklahoma State University, 264 McElroy Hall, Stillwater, OK 74078. E-mail: lin.liu{at}okstate.edu

Lung surfactant is secreted through the fusion of lamellar bodies with the plasma membrane of alveolar epithelial type II cells. Annexin A2, a Ca²⁺- and phospholipid-binding protein, promotes the fusion of lamellar bodies with the plasma membrane. Soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) are known to have an essential role in surfactant secretion. We hypothesized that annexin A2 acts as a Ca²⁺ sensor and mediates membrane fusion via its interaction with SNAREs. Both purified or endogenous annexin A2 in type II cells specifically bound with SNAP-23 in a Ca²⁺-dependent manner, as determined by pull-down experiments using recombinant glutathione S-transferase-tagged SNAP-23. A deletion study identified the cysteine-rich region (CRR) of SNAP-23 as the binding site for annexin A2. Mutations of cysteine residues in the CRR dramatically decreased the binding. SNAP-23 also co-immunoprecipitated with annexin A2; however, a SNAP-23 mutant failed to co-immunoprecipitate with annexin A2. Immunofluorescence revealed a co-localization of SNAP-23 and annexin A2 in type II cells. Furthermore, anti–SNAP-23 antibody significantly inhibited annexin A2–mediated fusion between lamellar bodies and the plasma membrane. These data suggest that annexin A2 and SNAP-23 are involved in the same pathway in the regulation of lung surfactant secretion.

Key Words: SNAP-23 • annexin A2 • lung surfactant • alveolar type II epithelial cells • membrane fusion

CLINICAL RELEVANCE Our work suggests that SNAP-23 and annexin A2 are involved in the same pathway in the regulation of lung surfactant secretion. These observations add to our knowledge of the mechanism of secretion and disease formation in type II epithelial cells.