Functional diversity of PH domains: an exhaustive modelling study.
BACKGROUND
Pleckstrin homology (PH) domains are found in many proteins involved in signal transduction or cytoskeletal organization. The general function for the domain is still unclear; phospholipid binding of some PH domains and a strong electrostatic polarization in the experimental structures suggest a role in localization on membranes. We have analyzed the electrostatic properties and the spatial amino acid distribution from homology models of the entire PH domain family.


RESULTS
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. but roughly half of the PH domains linked to a Dbl homology 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.


CONCLUSIONS
The mostly conserved electrostatic polarization supports a general function in binding to phospholipid membranes. But 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.
Blomberg
N
N
European Molecular Biology Laboratory, Heidelberg, Germany.
Nilges
M
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001792:Blood Platelets / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D003198:Computer Simulation; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry; D051379:Mice; D008870:Microtubules / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D054803:Phospholipase C delta; D010750:Phosphoproteins; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013049:Spectrin / Q000737:chemistry; D055672:Static Electricity; D010738:Type C Phospholipases / Q000737:chemistry
D000596:Amino Acids; D001798:Blood Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; C039077:platelet protein P47; D013049:Spectrin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D010738:Type C Phospholipases; D054803:Phospholipase C delta; D020558:GTP Phosphohydrolases; D034281:Dynamins