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J. Biol. Chem., Vol. 277, Issue 34, 30984-30990, August 23, 2002
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From the Departments of Human group IIA phospholipase
A2 (hGIIA) is secreted from a number of cells during
inflammation and is known to interact strongly with anionic membranes
and to exhibit potent Gram-positive bactericidal activity. This protein
contains 23 cationic residues, which are scattered over its entire
surface, resulting in a high pI of 9.39. To understand the molecular
basis for the selective binding of hGIIA to anionic membranes, 14 single-site, spin-labeled hGIIA proteins were analyzed in the presence
and absence of vesicles of anionic phospholipid by time domain and
continuous wave electron paramagnetic resonance (EPR) spin relaxant
techniques. Surprisingly, for hGIIA bound to anionic vesicles, all of
the spin labels were highly protected from water-soluble spin
relaxants. Together with light scattering studies, these EPR results
suggest the formation of a supramolecular aggregate involving clusters
of hGIIA molecules bridging together multiple vesicles. This anomalous
mode of binding of hGIIA to anionic phospholipid explains previous data
in which charge reversal mutation of a few cationic residues on
multiple faces of hGIIA leads to a comparable and modest reduction in
affinity of the protein for anionic vesicles. In the presence of mixed micelles composed of 10% anionic phospholipids in Triton X-100 a
monodisperse protein-lipid complex is formed. Under these conditions, the EPR methods were used to map the surface of hGIIA that constitutes the interfacial binding site (IBS). The IBS of hGIIA consists of the
highly hydrophobic surface that surrounds the opening to the active
site slot.
Unusual Mode of Binding of Human Group IIA Secreted
Phospholipase A2 to Anionic Interfaces as Studied by
Continuous Wave and Time Domain Electron Paramagnetic Resonance
Spectroscopy*
§¶,¶,§,
, and§
Chemistry and
§ Biochemistry, University of Washington,
Seattle, Washington 98195
*
This work was supported by Grants HL36235, HL50040, and
GM065944 from the National Institutes of Health. The Bruker EMX EPR spectrometer used for some CW measurements was funded under the UW
Environmental Sciences Center Grant P30-ESO7033 from the NIEHS.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests may be addressed:
Depts. of Chemistry and Biochemistry, Box 351700, University of
Washington, Seattle, WA 98195. E-mail: gelb@chem.washington.edu and
robinson@chem.washington.edu.
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