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.
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.
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