A structural model for the membrane-bound form of the juxtamembrane domain of the epidermal growth factor receptor

被引:42
作者
Choowongkomon, K
Carlin, CR
Sönnichsen, FD
机构
[1] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Rainbow Babies & Childrens Hosp, Rainbow Ctr Childhood PKD, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Ctr Canc, Cleveland, OH 44106 USA
[4] Cleveland Ctr Struct Biol, Cleveland, OH 44106 USA
关键词
D O I
10.1074/jbc.M502698200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (LL659)-L-658 motif, are responsible for basolateral sorting in polarized epithelial cells, and a (LL680)-L-679 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.
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页码:24043 / 24052
页数:10
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