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Vol. 14, Issue 7, 2935-2945, July 2003

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Essential role of Ca²⁺/Calmodulin in Early Endosome Antigen-1 Localization

Deirdre C. Lawe ^*, Nachida Sitouah ^*, Susan Hayes , Anil Chawla ^* , Joseph V. Virbasius ^* , Richard Tuft , Kevin Fogarty , Lawrence Lifshitz , David Lambright ^*  , and Silvia Corvera ^*  ||

^* Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 10615; Interdisciplinary Graduate Program, University of Massachusetts Medical School, Worcester, Massachusetts 10615; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 10615; and Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 10615

Submitted September 14, 2002; Revised February 14, 2003; Accepted February 15, 2003
Monitoring Editor: Keith Mostov

Ca²⁺ is an essential requirement in membrane fusion, acting through binding proteins such as calmodulin (CaM). Ca²⁺/CaM is required for early endosome fusion in vitro, however, the molecular basis for this requirement is unknown. An additional requirement for endosome fusion is the protein Early Endosome Antigen 1 (EEA1), and its recruitment to the endosome depends on phosphatidylinositol 3-phosphate [PI(3)P] and the Rab5 GTPase. Herein, we demonstrate that inhibition of Ca²⁺/CaM, by using either chemical inhibitors or specific antibodies directed to CaM, results in a profound inhibition of EEA1 binding to endosomal membranes both in live cells and in vitro. The concentration of Ca²⁺/CaM inhibitors required for a full dissociation of EEA1 from endosomal membranes had no effect on the activity of phosphatidylinositol 3-kinases or on endogenous levels of PI(3)P. However, the interaction of EEA1 with liposomes containing PI(3)P was decreased by Ca²⁺/CaM inhibitors. Thus, Ca²⁺/CaM seems to be required for the stable interaction of EEA1 with endosomal PI(3)P, perhaps by directly or indirectly stabilizing the quaternary organization of the C-terminal FYVE domain of EEA1. This requirement is likely to underlie at least in part the essential role of Ca²⁺/CaM in endosome fusion.

^|| Corresponding author. E-mail address: silvia.corvera{at}umassmed.edu.

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