Structural Basis for Discrimination of 3-phosphoinositides by Pleckstrin Homology Domains

Mol Cell. 2000 Aug;6(2):373-84. doi: 10.1016/s1097-2765(00)00037-x.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Binding Sites
  • Blood Proteins / chemistry
  • Blood Proteins / metabolism
  • Crystallography, X-Ray
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism
  • Hydrogen Bonding
  • Inositol Phosphates / metabolism*
  • Lipoproteins*
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / chemistry*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositols / metabolism*
  • Protein Structure, Secondary
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Substrate Specificity
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Blood Proteins
  • DAPP1 protein, human
  • Fatty Acids
  • Inositol Phosphates
  • Lipoproteins
  • Phosphatidylinositols
  • Phosphatidylinositol 3-Kinases

Associated data

  • PDB/1FAO
  • PDB/1FB8
  • PDB/1FHW
  • PDB/1FHX