Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains

Kathryn M. Ferguson, Jennifer M. Kavran, Vijay G. Sankaran, Emmanuel Fournier, Steven J. Isakoff, Edward Y. Skolnik, Mark A. Lemmon

Research output: Contribution to journalArticlepeer-review

Abstract

Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns (3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.

Original languageEnglish (US)
Pages (from-to)373-384
Number of pages12
JournalMolecular cell
Volume6
Issue number2
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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