Pleckstrin homology (PH) domain page

We have studied the pleckstrin homology (PH) domain family using homology based modelling as an extension of traditional sequence analysis techniques. The PH domain is a small (100-120 aa) module found in a multitude of intracellullar proteins with very widepread functions. Many of the PH domain containing proteins are found to participate in signalling cascades but there are also other classes of proteins such as cytoskeletal proteins (eg spectrin) that carry a PH domain.

The PH domain family is very divergent at a sequence level, the average pairwise identity is below 20%.  Despite this it is structurally very conserved  with the core secondary structure superimposing well and almost all variation confined to the loops. Generall, one would need a higher identity between such small proteins to be confident about structural  homology predictions and this remarkable structural conservation is one of the interesting features of this domain.
 

Modelling of the entire PH domain family:

We have analysed the electrostatic properties and spatial amino acid distribution from homology models built for the entire PH domain family.

Despite the sequence  divergence the quality of the models is sufficient for our study. Most PH domains have an electrostatic polarization similar to the experimental structures. However, roughly half of the PH domains linked to a Dbl-homology (DH) domain have very different electrostatic properties. We also found a striking electrostatic complementarity in some internal PH domain repeats. The analysis of the spatial distribution of amino acids identified residues in the phospholipid  binding site of the spectrin and dynamin PH domains as specific for these domains. 
The mostly conserved electrostatic polarization supports a general function in binding to phospholipid  membranes. However, the presence of PH-domains with opposite polarity suggests that ligands and functions have diverged during evolution. We also demonstrate homology modelling as a general sequence analysis tool that can yield significantly more information than conventional analysis.



Read more in our papers:


Supplementary material for the paper:

Take a look at the models:
Take a look at the contoured potentials:


If you have comments or suggestions, please send a mail to Michael Nilges

author: Niklas Blomberg
last update: August 23, 2001