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J. Biol. Chem., Vol. 280, Issue 10, 9595-9603, March 11, 2005

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Structure and Dynamics of Micelle-bound Human -Synuclein^*

Tobias S. Ulmer, Supported by a Long Term Fellowship from the Human Frontier Science Program Organization, Ad Bax, Nelson B. Cole¶, and Robert L. Nussbaum¶

From the Laboratory of Chemical Physics, NIDDK and the ^¶Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892

Misfolding of the protein -synuclein (aS), which associates with presynaptic vesicles, has been implicated in the molecular chain of events leading to Parkinson's disease. Here, the structure and dynamics of micelle-bound aS are reported. Val³-Val³⁷ and Lys⁴⁵-Thr⁹² form curved -helices, connected by a well ordered, extended linker in an unexpected anti-parallel arrangement, followed by another short extended region (Gly⁹³-Lys⁹⁷), overlapping the recently identified chaperone-mediated autophagy recognition motif and a highly mobile tail (Asp⁹⁸-Ala¹⁴⁰). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. Structural and dynamic parameters show a reduced helical content for Ala³⁰-Val³⁷. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the remarkably glycine-rich segments of the helices. These unusually rich dynamics may serve to mitigate the effect of aS binding on membrane fluidity. The well ordered conformation of the helix-helix connector indicates a defined interaction with lipidic surfaces, suggesting that, when bound to larger diameter synaptic vesicles, it can act as a switch between this structure and a previously proposed uninterrupted helix.

Received for publication, October 18, 2004 , and in revised form, December 13, 2004.

The atomic coordinates and structure factors (code 1XQ8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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 Figs. S1–S6.

To whom correspondence should be addressed. Tel.: 301-594-8301; Fax: 301-496-0825; E-mail: tobias.ulmer{at}nih.gov.

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