PROTEIN DOMAINS HOMOLOGOUS TO PLECKSTRIN REPEATS

Pleckstrin is the major substrate of protein kinase C in platelets. Ex pression cloning of pleckstrin yielded a cDNA encoding a protein with two internal repeats of about 120 aminoacids located at the N and C te rminal extremities of the molecule. Database screening led to discover the presence of domains homologous to the pleckstrin repeats in more than 90 proteins devoid of common physiological function such as serin e-threonine or tyrosine protein kinases, phospholipases, membrane and cytoskeletal proteins and many signaling proteins including activators and inhibitors of small G-protein. Some of them, especially the signa ling proteins contain other homology domains such as SH2, SH3 and Dbl. All PH domains share a common tridimensional structure characterized by a seven-stranded antiparallel beta-sheet and a strong bend forming an orthogonal sandwich which is closed by a C-terminal alpha-helix. Th e PH structures differ most in the loop regions between beta strands w here more or less large insertions may be present. All PH domains cont ain a positively charged region towards the N-terminal of the domain. Most of the PH-containing proteins should be hound or approached to th e cell membrane for assuming their function. The PH domains can be bou nd to the membrane through interaction of the positively charged regio n with the negatively charged phosphoinositides. Phospholipase C delta 1 (PLC delta 1) binds its membrane substrate (PdIns 4,5) P2 through i ts PH domain with high specificity. Phosphoinositides are the main lig ands of the PH domains. However C-terminal region of some PH domains b inds the gamma component of the trimeric G proteins. PPI Domains could be anchored to the membrane by both phosphoinositols and G gamma prot eins, Very probably other as yet unidentified ligands interact with th e PH domains. Several different mutations in the PH domain of the Brut on tyrosine kinase are responsible of some cases of X-linked agammaglo bulinemia in man and mice. At the present day they are the sole PH dom ain mutations associated with diseased state.