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J. Biol. Chem., Vol. 281, Issue 11, 7515-7525, March 17, 2006

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Interaction of Surfactant Protein A with Peroxiredoxin 6 Regulates Phospholipase A₂ Activity^*

From the Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6068

Peroxiredoxin 6 (Prdx6) is a "moonlighting" protein with both GSH peroxidase and phospholipase A₂ (PLA₂) activities. This protein is responsible for degradation of internalized dipalmitoylphosphatidylcholine, the major phospholipid component of lung surfactant. The PLA₂ activity is inhibited by surfactant protein A (SP-A). We postulate that SP-A regulates the PLA₂ activity of Prdx6 through direct protein-protein interaction. Recombinant human Prdx6 and SP-A isolated from human alveolar proteinosis fluid were studied. Measurement of kinetic constants at pH 4.0 (maximal PLA₂ activity) showed K_m0.35 mM and V_max 138 nmol/min/mg of protein. SP-A inhibited PLA₂ activity non-competitively with K_i 10 µg/ml and was Ca²⁺ -independent. Activity at pH 7.4 was 50% less, and inhibition by SP-A was partially dependent on Ca²⁺. Interaction of SP-A and Prdx6 at pH 7.4 was shown by Prdx6-mediated inhibition of SP-A binding to agarose beads, a pull-down assay using His-tagged Prdx6 and Ni² -chelating beads, co-immunoprecipitation from lung epithelial cells and from a binary mixture of the two proteins, binding after treatment with a trifunctional cross-linker, and size-exclusion chromatography. Analysis by static light scattering and surface plasmon resonance showed calcium-independent SP-A binding to Prdx6 at pH 4.0 and partial Ca²⁺ dependence of binding at pH 7.4. These results indicate a direct interaction between SP-A and Prdx6, which provides a mechanism for regulation of the PLA₂ activity of Prdx6 by SP-A.

Received for publication, April 25, 2005 , and in revised form, November 28, 2005.

^* This work was supported by Grant HL19737 from the National Institutes of Health. The results of this study have been presented in part at EB2004 in Washington, DC and EB2005 in San Diego, CA. 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: Institute for Environmental Medicine, University of Pennsylvania, One John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068. Tel.: 215-898-9108; Fax: 215-898-0868; E-mail: abf{at}mail.med.upenn.eduX.

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