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J. Biol. Chem., Vol. 281, Issue 15, 10448-10460, April 14, 2006
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-Chain Is Controlled by a Multicomponent Intracellular Retention Signal*
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
The human high affinity IgE receptor (Fc
RI) is a central component of the allergic response and is expressed as either a trimeric 
2 or tetrameric 

2 complex. It has been previously described that the cytoplasmic domain (CD) of the
-chain carries a dilysine motif at positions -3/-7 from the C terminus that functions in intracellular retention prior to assembly with other Fc
RI subunits. In this report we have further explored the role of the -3/-7 dilysine signal in controlling steady-state
-chain transport by mutational analysis and found little surface expression of a -3/-7 dialanine
-chain mutant but significant Golgi localization. We compared the transport properties of a series of
-chain cytoplasmic domain truncation mutants and observed that truncation mutants lacking 23 or more C-terminal residues showed a dramatic increase in steady-state transport suggesting a role for the membrane-proximal CD sequence in
-chain retention. By performing alanine-scanning mutagenesis we identified a dilysine sequence (Lys212-Lys216) proximal to the transmembrane domain (TMD) that is important for both
-chain cell-surface expression and intracellular stability. Furthermore, co-mutation of the Lys212-Lys216 residues with the -3/-7 dilysine signal produced a dramatic increase in
-chain surface expression that was further increased by co-mutation of the lone charged residue (Asp192) in the TMD thereby defining three regions that function to regulate
-chain transport and in a highly synergistic manner.
Received for publication, October 3, 2005 , and in revised form, February 1, 2006.
* This work was supported by Grant RO1-AI47238 from NIAID, National Institutes of Health. The oligonucleotides used in this study were partially funded through the Sam and Rose Stein Endowment Fund. This was manuscript number 17761-MEM from the Scripps Research Institute. 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.
1 To whom correspondence should be addressed: Dept. of Molecular and Experimental Medicine, MEM-131, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Tel.: 858-784-9221; Fax: 858-784-2131; E-mail: mwr{at}scripps.edu.
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