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J. Biol. Chem., Vol. 282, Issue 13, 9996-10004, March 30, 2007

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Annexin B12 Is a Sensor of Membrane Curvature and Undergoes Major Curvature-dependent Structural Changes^*

Torsten Fischer, Lucy Lu, Harry T. Haigler¹, and Ralf Langen²

From the Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033 and the Department of Physiology and Biophysics, University of California, Irvine, California 92697

The regulation of membrane curvature plays an important role in many membrane trafficking and fusion events. Recent studies have begun to identify some of the proteins involved in controlling and sensing the curvature of cellular membranes. A mechanistic understanding of these processes is limited, however, as structural information for the membrane-bound forms of these proteins is scarce. Here, we employed a combination of biochemical and biophysical approaches to study the interaction of annexin B12 with membranes of different curvatures. We observed selective and Ca²⁺-independent binding of annexin B12 to negatively charged vesicles that were either highly curved or that contained lipids with negative intrinsic curvature. This novel curvature-dependent membrane interaction induced major structural rearrangements in the protein and resulted in a backbone fold that was different from that of the well characterized Ca²⁺-dependent membrane-bound form of annexin B12. Following curvature-dependent membrane interaction, the protein retained a predominantly -helical structure but EPR spectroscopy studies of nitroxide side chains placed at selected sites on annexin B12 showed that the protein underwent inside-out refolding that brought previously buried hydrophobic residues into contact with the membrane. These structural changes were reminiscent of those previously observed following Ca²⁺-independent interaction of annexins with membranes at mildly acidic pH, yet they occurred at neutral pH in the presence of curved membranes. The present data demonstrate that annexin B12 is a sensor of membrane curvature and that membrane curvature can trigger large scale conformational changes. We speculate that membrane curvature could be a physiological signal that induces the previously reported Ca²⁺-independent membrane interaction of annexins in vivo.

Received for publication, December 6, 2006 , and in revised form, January 30, 2007.

^* This work was supported by National Institutes of Health Grants GM 63915 (to R. L.) and GM 55651 (to H. T. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence may be addressed. Tel.: 949-824-8304; E-mail: hhaigler{at}uci.edu.

² To whom correspondence may be addressed. Tel.: 323-442-1323; E-mail: langen{at}usc.edu.

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