Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 37, Pages 13052-13057Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503900102
Keywords
phosphoinositide; early endosome antigen 1
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BBS/B/10714] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/B/10714] Funding Source: Medline
- Wellcome Trust [071684] Funding Source: Medline
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Specific recognition of phosphatidylinositol 3-phosphate [PtdIns(3)P] by the FYVE domain targets cytosolic proteins to enclosomal 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 enclosomal 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 P40(phox) 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 enclosomal membranes.
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