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PH domain

Class: Phospholipid Binding

Brief description: The pleckstrin homology (PH) domain, first identified as a 100-120-residues, was originally proposed to be involved in protein-protein interactions in cellular signalling. Subsequent work has shown that many PH domains direct membrane targeting of their host proteins, but by binding to phosphoinositides rather than proteins in cellular membranes. Of a large number of PH domains detected in protein sequences, functions of only a few have been convincingly demonstrated. In these cases, the PH domain binds with high affiniy and specifiity to a phosphoinositide (such as PI(4,5)P2). In other cases, the ligands are the products of agonist-stimulated phosphoinositide 3-kinases (PI3-kinases).

Structure:

structure Unlike other membrane-targeting domains, PH domains do not have a deep lipid-binding pocket. A line of aromatic or hydrophobic residues is also missing. Although they display diversity in primary sequences, PH domains share a conserved fold which is made up of a b-barrel composed of two roughly perpendicular, anti-parallel beta-sheets and an alpha-helix. The b-sheets curve in a tight barrel-like conformation while helix folds to cover one end of the barrel. The interstrand loops are involved in ligand binding. Basic residues in these loops are important for binding the phosphatidylinositide phosphates, by establishing a positive electric potential on the face of the PH domain. Binding of PH domains in driven initially by non-specific electrostatic interaction followed by specific lipid recongnition.

Subcellular Localization:

In a phosphoinositide-dependent manner, many PH domains drive the host protein to PI-rich membranes. For example, PH domain of PLCd1 drives the enzyme enzyme to the plasma membrane. PH domain of Akt/PKB recruits the protein to the PtdIns(3,4,5)P3 site in the plasma membrane. The PH domain of the ß-adrenergic receptor kinase, which has low PtdIns(4,5)P2 affinity, drives the membrane targeting of the host protein.

Get the sequences in a Swiss-Prot/Uniprot pattern and Tab-delimited format.

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Relevant Literature

1. Lemmon, M.A. and Ferguson, K.M. (2000) Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochem J, 350 Pt 1, 1-18.

2. Lemmon, M.A. (2007) Pleckstrin homology (PH) domains and phosphoinositides. Biochem Soc Symp, 81-93.

3. Cozier, G.E., Carlton, J., Bouyoucef, D. and Cullen, P.J. (2004) Membrane targeting by pleckstrin homology domains. Curr Top Microbiol Immunol, 282, 49-88.

4. Chang, J.S., Kim, S.K., Kwon, T.K., Bae, S.S., Min, D.S., Lee, Y.H., Kim, S.O., Seo, J.K., Choi, J.H. and Suh, P.G. (2005) Pleckstrin homology domains of phospholipase C-gamma1 directly interact with beta-tubulin for activation of phospholipase C-gamma1 and reciprocal modulation of beta-tubulin function in microtubule assembly. J Biol Chem, 280, 6897-6905.