Structural characterization of the interaction between a pleckstrin homology domain and phosphatidylinositol 4,5-bisphosphate.

Harlan JE, Yoon HS, Hajduk PJ, Fesik SW
Biochemistry. 1995 34 (31): 9859-64

PMID: 7632686 · DOI:10.1021/bi00031a006

The pleckstrin homology (PH) domain is a protein module of approximately 100 amino acids that is found in several proteins involved in signal transduction [for a recent review, see Gibson et al. (1994) Trends Biochem. Sci. 19, 349-353]. Although the specific function of the PH domain has not yet been elucidated, many of the proteins which contain this domain associate with phospholipid membranes, and PH domains have been shown to bind to phosphatidylinositol 4,5-bisphosphate (PIP2) [Harlan et al. (1994) Nature 371, 168-170] and the beta gamma subunits of G-proteins [Touhara et al. (1994) J. Biol. Chem. 269, 10217-10220]. We have postulated that pleckstrin homology domains may be important for the translocation of proteins to the membrane by an interaction with the negatively charged head group of phospholipids. Here we show the importance of three conserved lysine residues for binding to PIP2 by site-directed mutagenesis. These results should aid future site-directed mutagenesis studies in probing the function of PIP2-PH domain interactions in the various proteins containing this module. In addition, we examine the specificity of this binding and illustrate the importance of charge--charge interactions in PIP2-PH domain complex formation from binding experiments involving PIP2 analogs.

MeSH Terms (14)

Amino Acid Sequence Base Sequence Binding Sites Blood Proteins Lysine Molecular Sequence Data Mutagenesis, Site-Directed Peptide Fragments Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphoproteins Protein Conformation Sequence Alignment Sequence Homology, Amino Acid

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