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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 (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 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).
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2 subunit (green). The other site (red circle labeled 1) is within the µ2 subunit (brown). Binding of the lipid to this site is believed to be one of the factors inducing a conformational change that allows binding of the internalization motif Yxx
to µ2 at a site that is otherwise blocked by interaction with the ß2 subunit (gray circle labeled 2). (B) The binding of Ins(1,4,5)P3 [mimicking PtdIns(4,5)P2] to CALM occurs at a helical domain (green) in a similarly peripheral position to that seen in AP-2. By contrast, in the ENTH domain of epsin, an additional helix (helix 0), which is disordered in the structure without the inositide, contributes to the coordination of the lipid headgroup within the multi-helical structure that is otherwise very similar to CALM/ANTH domains. (C) The structure of ß-arrestin-1 resembles that of the C-terminal multi-stranded domain of the AP-2 µ2 subunit. The electropositive groove that interacts with phosphorylated tails of G protein-coupled receptors (gray circle labeled 2) and the adjacent inositide-binding pocket (red circle labeled 1) are very reminiscent of the peptide- and lipid-binding sites of the AP-2 µ2 domain. Gray arrows indicate clathrin- and ß2-adaptin-binding sites. The PDB accession numbers used are: 1GW5