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J. Biol. Chem., Vol. 282, Issue 20, 15057-15064, May 18, 2007

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Intrinsic Disorder and Autonomous Domain Function in the Multifunctional Nuclear Protein, MeCP2^*

Valerie H. Adams, Steven J. McBryant, Paul A. Wade, Christopher L. Woodcock^¶, and Jeffrey C. Hansen¹

From the Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, the ^¶Department of Biology, University of Massachusetts, Amherst, Massachusetts 01003, and the Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

To probe the tertiary structure and domain organization of native methyl CpG-binding protein 2 (MeCP2), the recombinant human e2 isoform was purified to homogeneity and characterized by analytical ultracentrifugation, CD, and protease digestion. The location of intrinsic disorder in the MeCP2 sequence was predicted using the FoldIndex algorithm. MeCP2 was found to be monomeric in low and high salt and over a nearly 1000-fold concentration range. CD indicated that the MeCP2 monomer was nearly 60% unstructured under conditions where it could preferentially recognize CpG dinucleotides and condense chromatin. Protease digestion experiments demonstrate that MeCP2 is composed of at least six structurally distinct domains, two of which correspond to the well characterized methyl DNA binding domain and transcriptional repression domain. These domains collectively are organized into a tertiary structure with coil-like hydrodynamic properties, reflecting the extensive disorder in the MeCP2 sequence. When expressed as individual fragments, the methyl DNA binding domain and transcriptional repression domain both could function as nonspecific DNA binding domains. The unusual structural features of MeCP2 provide a basis for understanding MeCP2 multifunctionality in vitro and in vivo. These studies also establish an experimental paradigm for characterizing the tertiary structures of other highly disordered proteins.

Received for publication, January 30, 2007 , and in revised form, March 12, 2007.

^* This work was supported by individual grants from the Rett Syndrome Research Foundation (to P. W., J. C. H., and C. W.), National Institutes of Health Grants GM45916 and GM66834 (to J. H.) and GM70897 (to C. W.), and grants from the Intramural Research Program of NIEHS, National Institutes of Health (to P. W.). 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 three supplemental figures.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Colorado State University, 1870 Campus Delivery, Fort Collins, CO 80523. Tel.: 970-491-5586; Fax: 970-491-0494; E-mail: Jeffrey.C.Hansen{at}colostate.edu.

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