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Fig. 1. Similarities and differences between the inositide and peptide binding of PH, PTB, PDZ and FERM domains. (A) Inositide binding of PH domains occurs in a pocket formed by the ß1-ß4 sheets and connecting loops (light blue). Exceptions are the spectrin PH domain, which binds the lipid outside this position, and the Grp1/ARNO PH domain, in which a long insertion (brown) replaces the ß3-ß4 sheets in forming the pocket. The position of Gß{gamma} (gray) bound to the GRK2 PH domain shows that it involves a surface distinct from the putative lipid-binding site (purple arrow). (B) PTB domains often contain a helix inserted between their ß1-ß2 strands (salmon). Inositol lipids bind at the outer surface of this helix (the purple arrow indicates the presumed lipid-binding site of Shc), whereas the peptide always binds between the C-terminal helix and the parallel ß7 strand. (C) The C-subdomain of FERM domains is a PTB fold that binds peptide sequences found within integrin tails. The inositide binding site of radexin is quite far from the inositide-binding site of PH domains, but mutagenesis studies indicate an additional binding site in radexin talin and moesin (purple arrows) that corresponds to the region where PH domains bind inositides. This putative lipid-binding site is masked by the C-terminal tail in the inactive conformation of moesin. (D) The PDZ domain binds its peptide binding-partners at a position similar to that in the PTB domains. The kink in the loop between the ß1 and ß2 strand explains why PDZ domains usually bind C-terminal peptides. The only reported inositide binding of the Syntenin PH domain maps to a surface pointed to by the purple arrow. The PDB accession numbers used were: 1MAI, PLC{theta}1PH (Ferguson et al., 1995); 1H10, AktPH (Thomas et al., 2002);1BTN, SpectrinPH (Hyvonen et al., 1995); 1FHX, Grp1PH (Ferguson et al., 2000); 1OMW, GRK2PH (Lodowski et al., 2003); 1NU2, Dab1PTB (Stolt et al., 2003); 1SHC, ShcPTB (Zhou et al., 1995); 1IRS, IRS1PTB (Zhou et al., 1996); 1BE9, PSD95PDZ3 (Morais-Cabral et al., 1996); 1OBX, SyntheninPDZ2 (Kang et al., 2003); 1GC6, Radixin-FERM-InsP3 (Hamada et al., 2000); 1J19, Radixin-FERM-ICAM2pept (Hamada et al., 2003); 1MK7, Talin-FERM (Garcia-Alvarez et al., 2003); 1SGH, Moesin-FERM (Finnerty et al., 2004). Pictures were created by Molscript (Kraulis, 1991).