A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains

Lucia E. Rameh, Ann Kristin Arvidsson, Kermit L Carraway, Anthony D. Couvillon, Gary Rathbun, Anne Crompton, Barbara VanRenterghem, Michael P. Czech, Kodimangalam S. Ravichandran, Steven J. Burakoff, Da Sheng Wang, Ching Shih Chen, Lewis C. Cantley

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411 Scopus citations

Abstract

Pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains are structurally related regulatory modules that are present in a variety of proteins involved in signal transduction, such as kinases, phospho-lipases, GTP exchange proteins, and adapter proteins. Initially these domains were shown to mediate protein protein interactions, but more recently they were also found to bind phosphoinositides. Most studies to date have focused on binding of PH domains to phosphatidylinositol (PtdIns)-4-P and PtdIns-4,5- P2 and have not considered the lipid products of phosphoinositide 3-kinase: PtdIns-3-P, PtdIns-3,4-P2, and PtdIns-3,4,5-P3. Here we have compared the phosphoinositide specificity of six different PH domains and the Shc PTB domain using all five phosphoinositides. We show that the Bruton's tyrosine kinase PH domain binds to PtdIns-3,4,5-P3 with higher affinity than to PtdIns-4,5-P2, PtdIns-3,4-P2 or inositol 1,3,4,5-tetrakisphosphate (Ins- 1,3,4,5-P4). This selectivity is decreased by the xid mutation (R28C). Selective binding of PtdIns-3,4,5-P3 over PtdIns-4,5-P2 or PtdIns-3,4-P2 was also observed for the amino-terminal PH domain of T lymphoma invasion and metastasis protein (Tiam-1), the PH domains of Son-of-sevenless (Sos) and, to a lesser extent, the PH domain of the β-adrenergic receptor kinase. The oxysterol binding protein and β-spectrin PH domains bound PtdIns-3,4,5-P3 and PtdIns-4,5-P2 with similar affinities. PtdIns-3,4,5-P3 and PtdIns-4,5- P2 also bound to the PTB domain of Shc with similar affinities and lipid binding was competed with phosphotyrosine (Tyr(P)-containing peptides. These results indicate that distinct PH domains select for different phosphoinositides.

Original languageEnglish (US)
Pages (from-to)22059-22066
Number of pages8
JournalJournal of Biological Chemistry
Volume272
Issue number35
DOIs
StatePublished - Aug 29 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Rameh, L. E., Arvidsson, A. K., Carraway, K. L., Couvillon, A. D., Rathbun, G., Crompton, A., VanRenterghem, B., Czech, M. P., Ravichandran, K. S., Burakoff, S. J., Wang, D. S., Chen, C. S., & Cantley, L. C. (1997). A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. Journal of Biological Chemistry, 272(35), 22059-22066. https://doi.org/10.1074/jbc.272.35.22059