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J. Biol. Chem., Vol. 280, Issue 44, 36773-36783, November 4, 2005

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Evidence for the Regulatory Role of the N-terminal Helix of Secretory Phospholipase A₂ from Studies on Native and Chimeric Proteins^*

Shan Qin, Abhay H. Pande, Kathleen N. Nemec, Xiaomei He¶, and Suren A. Tatulian1

From the Biomolecular Science Center, University of Central Florida, Orlando, Florida 32826, the Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and the ^¶ Department of Chemistry, University of Central Florida, Orlando, Florida 32816

The phospholipase A₂ (PLA₂) enzymes are activated by binding to phospholipid membranes. Although the N-terminal -helix of group I/II PLA₂s plays an important role in the productive mode membrane binding of the enzymes, its role in the structural aspects of membrane-induced activation of PLA₂s is not well understood. In order to elucidate membrane-induced conformational changes in the N-terminal helix and in the rest of the PLA₂, we have created semisynthetic human group IB PLA₂ in which the N-terminal decapeptide is joined with the ¹³C-labeled fragment, as well as a chimeric protein containing the N-terminal decapeptide from human group IIA PLA₂ joined with a ¹³C-labeled fragment of group IB PLA₂. Infrared spectral resolution of the unlabeled and ¹³C-labeled segments suggests that the N-terminal helix of membrane-bound IB PLA₂ has a more rigid structure than the other helices. On the other hand, the overall structure of the chimeric PLA₂ is more rigid than that of the IB PLA₂, but the N-terminal helix is more flexible. A combination of homology modeling and polarized infrared spectroscopy provides the structure of membrane-bound chimeric PLA₂, which demonstrates remarkable similarity but also distinct differences compared with that of IB PLA₂. Correlation is delineated between structural and membrane binding properties of PLA₂s and their N-terminal helices. Altogether, the data provide evidence that the N-terminal helix of group I/II PLA₂s acts as a regulatory domain that mediates interfacial activation of these enzymes.

Received for publication, June 22, 2005 , and in revised form, August 4, 2005.

^* This work was supported by NHLBI Grant HL65524 from the National Institutes of Health. 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: Biomolecular Science Center, University of Central Florida, 12722 Research Pkwy., Orlando, FL 32826. Fax: 407-384-2062; E-mail: statulia{at}mail.ucf.edu.

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