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J. Biol. Chem., Vol. 280, Issue 25, 24043-24052, June 24, 2005

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A Structural Model for the Membrane-bound Form of the Juxtamembrane Domain of the Epidermal Growth Factor Receptor^*

Kiattawee Choowongkomon, Cathleen R. Carlin¶, and Frank D. Sönnichsen¶||**

From the Department of Physiology and Biophysics, Case Western Reserve University, The Rainbow Center for Childhood PKD, Rainbow Babies & Children's Hospital, the ^¶Case Western Reserve University Cancer Center, and the ^||Cleveland Center for Structural Biology, Cleveland, Ohio 44106

The epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinase family involved in the regulation of cellular proliferation and differentiation. Its juxtamembrane domain (JX), the region located between the transmembrane and kinase domains, plays important roles in receptor trafficking. Two sorting signals, a PXXP motif and a ⁶⁵⁸LL⁶⁵⁹ motif, are responsible for basolateral sorting in polarized epithelial cells, and a ⁶⁷⁹LL⁶⁸⁰ motif targets the ligand-activated receptor for lysosomal degradation. To understand the regulation of these signals, we characterized the structural properties of recombinant JX domain in aqueous solution and in dodecylphosphocholine (DPC) detergent. JX is inherently unstructured in aqueous solution, albeit a nascent helix encompasses the lysosomal sorting signal. In DPC micelles, structures derived from NMR data showed three amphipathic, helical segments. A large, internally inconsistent group of long range nuclear Overhauser effects suggest a close proximity of the helices, and the presence of significant conformational averaging. Models were determined for the average JX conformation using restraints representing the translational restriction due to micelle-surface adsorption, and the helix orientations were determined from residual dipolar couplings. Two equivalent average structural models were obtained that differ only in the relative orientation between first and second helices. In these models, the ⁶⁵⁸LL⁶⁵⁹ and ⁶⁷⁹LL⁶⁸⁰ motifs are located in the first and second helices and face the micelle surface, whereas the PXXP motif is located in a flexible helix-connecting region. The data suggest that the activity of these signals may be regulated by their membrane association and restricted accessibility in the intact receptor.

Received for publication, March 11, 2005 , and in revised form, April 19, 2005.

The atomic coordinates (code 1Z9I) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work were supported by National Institutes of Health Grant DK54178 (to C. R. C. and F. D. S.) and by a grant from the March of Dimes Birth Defects Foundation (to C. R. C.). Parts of this research were performed in the Environmental Molecular Sciences Laboratory (a national scientific user facility sponsored by the U.S. DOE Office of Biological and Environmental Research) located at Pacific Northwest National Laboratory, operated by Battelle for the DOE. 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.

^** To whom correspondence should be addressed: Dept. of Physiology and Biophysics, School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4970. Tel.: 216-368-5405; Fax: 216-368-1693; E-mail: fds{at}case.edu.

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