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J. Biol. Chem., Vol. 282, Issue 47, 34555-34567, November 23, 2007

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Conformation-specific Binding of -Synuclein to Novel Protein Partners Detected by Phage Display and NMR Spectroscopy^*

Wendy S. Woods, John M. Boettcher, Donghua H. Zhou, Kathryn D. Kloepper, Kevin L. Hartman, Daniel T. Ladror, Zhi Qi^¶, Chad M. Rienstra^¶, and Julia M. George¹

From the Department of Molecular and Integrative Physiology, the Department of Chemistry, and ^¶Center for Biophysics and Computational Biology, University of Illinois, Urbana, Illinois 61801

-Synuclein (AS) is an intrinsically unstructured protein in aqueous solution but is capable of forming -sheet-rich fibrils that accumulate as intracytoplasmic inclusions in Parkinson disease and certain other neurological disorders. However, AS binding to phospholipid membranes leads to a distinct change in protein conformation, stabilizing an extended amphipathic -helical domain reminiscent of the exchangeable apolipoproteins. To better understand the significance of this conformational change, we devised a novel bacteriophage display screen to identify protein binding partners of helical AS and have identified 20 proteins with roles in diverse cellular processes related to membrane trafficking, ion channel modulation, redox metabolism, and gene regulation. To verify that the screen identifies proteins with specificity for helical AS, we further characterized one of these candidates, endosulfine (ENSA), a small cAMP-regulated phosphoprotein implicated in the regulation of insulin secretion but also expressed abundantly in the brain. We used solution NMR to probe the interaction between ENSA and AS on the surface of SDS micelles. Chemical shift perturbation mapping experiments indicate that ENSA interacts specifically with residues in the N-terminal helical domain of AS in the presence of SDS but not in aqueous buffer lacking SDS. The ENSA-related protein ARPP-19 (cAMP-regulated phosphoprotein 19) also displays specific interactions with helical AS. These results confirm that the helical N terminus of AS can mediate specific interactions with other proteins and suggest that membrane binding may regulate the physiological activity of AS in vivo.

Received for publication, June 27, 2007 , and in revised form, August 31, 2007.

^* This work was supported by grants from the Branfman Family Foundation (to J. M. G.); NIA, National Institutes of Health, Grant R01 AG13762 (to J. M. G.); the American Parkinson Disease Association (to C. M. R.); and a Research Corporation Cottrell Scholars Award (to C. M. R.). 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 Table 1 and Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801. Tel.: 217-244-4525; Fax: 214-648-6899; E-mail: j-george{at}uiuc.edu.

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