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J. Biol. Chem., Vol. 283, Issue 23, 15656-15664, June 6, 2008

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Structural and Functional Consequences of Tyrosine Phosphorylation in the LRP1 Cytoplasmic Domain^*

Gina N. Betts, Peter van der Geer, and Elizabeth A. Komives¹

From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0378 and the Department of Chemistry, San Diego State University, San Diego, California 92182-1030

The cytoplasmic domain of LRP1 contains two NPXY motifs that have been shown to interact with signaling proteins. In previous work, we showed that Tyr⁴⁵⁰⁷ in the distal NPXY motif is phosphorylated by v-Src, whereas denaturation of the protein was required for phosphorylation of Tyr⁴⁴⁷³ in the membraneproximal NPXY motif. Amide H/D exchange studies reveal that the distal NPXY motif is fully solvent-exposed, whereas the proximal one is not. Phosphopeptide mapping combined with in vitro and in vivo kinase experiments show that Tyr⁴⁴⁷³ can be phosphorylated, but only if Tyr⁴⁵⁰⁷ is phosphorylated or substituted with glutamic acid. Amide H/D exchange experiments indicate that solvent accessibility increases across the entire LRP1 cytoplasmic region upon phosphorylation at Tyr⁴⁵⁰⁷; in particular the NPXY⁴⁴⁷³ motif becomes much more exposed. This differential phosphorylation is functionally relevant: binding of Snx17, which is known to bind at the proximal NPXY motif, is inhibited by phosphorylation at Tyr⁴⁴⁷³. Conversely, Shp2 binds most strongly when both of the NPXY motifs in LRP1 are phosphorylated.

Received for publication, November 20, 2007 , and in revised form, February 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG025343 and CA78629. This work was also supported by NIH Training Grant T32-DK07233 (to G. N. B.). 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 Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0378. Tel.: 858-534-3058; Fax: 858-534-6174; E-mail: ekomives{at}ucsd.edu.

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