A phosphoinositide-binding sequence is shared by PH domain target molecules--a model for the binding of PH domains to proteins.
Pleckstrin homology (PH) domains have been proven to bind phosphoinositides (PI) and inositolphosphates (IP). On the other hand, a binding of PH domains to proteins is still a matter of debate. The goal of this work was to identify potential PH domain protein target sites and to build a model for PH domain-protein binding. A candidate sequence, called HIKE, was identified by sequence homology analysis of the proteins that are considered the strongest PH binding candidates, i.e., Gbeta, PKC, and Akt. HIKE contains a PI binding sequence and fulfills several criteria for a potential PH-binding site, i.e., it is present in other PH-binding candidates, lies in regulatory regions independently predicted to bind PH domains, and is conserved in 3-D structure among different molecules. These findings and the similarities with the mode of binding of PTB and PDZ domains suggest a beta strand-beta strand coordination model for PH-protein binding. The HIKE model predicts that membrane anchoring of PH domains and their targets could be a critical step in their interaction, which would consistently explain why PH-protein binding has only been detected in the presence of PI.
Alberti
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Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Chieti, Italy. alberti@cmns.mnegri.it
D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000737:chemistry* / Q000378:metabolism*; D016384:Consensus Sequence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000737:chemistry* / Q000378:metabolism*; D010750:Phosphoproteins; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
D001798:Blood Proteins; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D011506:Proteins; C039077:platelet protein P47