Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch

Stephanie A. Lee, Rosemary Eyeson, Matthew L. Cheever, Jinming Geng, Vladislav Verkhusha, Christopher Burd, Michael Overduin, Tatiana G. Kutateladze

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Specific recognition of phosphatidylinositol 3-phosphate [PtdIns(3)P] by the FYVE domain targets cytosolic proteins to endosomal membranes during key signaling and trafficking events within eukaryotic cells. Here, we show that this membrane targeting is regulated by the acidic cellular environment. Lowering the cytosolic pH enhances PtdIns(3)P affinity of the FYVE domain, reinforcing the anchoring of early endosome antigen 1 (EEA1) to endosomal membranes. Reversibly, increasing the pH disrupts phosphoinositide binding and leads to cytoplasmic redistribution of EEA1. pH dependency is due to a pair of conserved His residues, the successive protonation of which is required for PtdIns(3)P head group recognition as revealed by NMR. Substitution of the His residues abolishes PtdIns(3)P binding by the FYVE domain in vitro and in vivo. Another PtdIns(3)P-binding module, the PX domain of Vam7 and p40phox is shown to be pH-independent. This provides the fundamental functional distinction between the two phosphoinositide-recognizing domains. The presented mode of FYVE regulation establishes the unique function of FYVE proteins as low pH sensors of PtdIns(3)P and reveals the critical role of the histidine switch in targeting of these proteins to endosomal membranes.

Original languageEnglish (US)
Pages (from-to)13052-13057
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number37
DOIs
StatePublished - Sep 13 2005
Externally publishedYes

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Histidine
Membranes
Phosphatidylinositols
Eukaryotic Cells
Protein Transport
phosphatidylinositol 3-phosphate
Proteins

Keywords

  • Early endosome antigen 1
  • Phosphoinositide

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch. / Lee, Stephanie A.; Eyeson, Rosemary; Cheever, Matthew L.; Geng, Jinming; Verkhusha, Vladislav; Burd, Christopher; Overduin, Michael; Kutateladze, Tatiana G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 37, 13.09.2005, p. 13052-13057.

Research output: Contribution to journalArticle

Lee, Stephanie A. ; Eyeson, Rosemary ; Cheever, Matthew L. ; Geng, Jinming ; Verkhusha, Vladislav ; Burd, Christopher ; Overduin, Michael ; Kutateladze, Tatiana G. / Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 37. pp. 13052-13057.
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