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J. Biol. Chem., Vol. 279, Issue 7, 5958-5966, February 13, 2004

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Structural Basis for Endosomal Targeting by FYVE Domains^*

Akira Hayakawa, Susan J. Hayes, Deirdre C. Lawe, Eathiraj Sudharshan, Richard Tuft¶, Kevin Fogarty¶, David Lambright||, and Silvia Corvera**

From the Program in Molecular Medicine, Interdisciplinary Graduate Program, and the Departments of ^¶Biochemistry and Molecular Pharmacology and ^||Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

The FYVE domain is a conserved protein motif characterized by its ability to bind with high affinity and specificity to phosphatidylinositol 3-phosphate (PI(3)P), a phosphoinositide highly enriched in early endosomes. The PI(3)P polar head group contacts specific amino acid residues that are conserved among FYVE domains. Despite full conservation of these residues, the ability of different FYVE domains to bind to endosomes in cells is highly variable. Here we show that the endosomal localization in intact cells absolutely requires structural features intrinsic to the FYVE domain in addition to the PI(3)P binding pocket. These features are involved in FYVE domain dimerization and in interaction with the membrane bilayer. These interactions, which are determined by non-conserved residues, are likely to be essential for the temporal and spatial control of protein associations at the membrane-cytosol interface within the endocytic pathway.

Received for publication, September 23, 2003 , and in revised form, October 28, 2003.

^* This work was supported by National Institutes of Health Grants DK54479 and DK60564. 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: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St., Ste. 107, Worcester, MA 01605. E-mail: silvia.corvera{at}umassmed.edu.

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