Non-canonical Interaction of Phosphoinositides with Pleckstrin Homology Domains of Tiam1 and ArhGAP9

Pleckstrin homology (PH) domains are phosphoinositide (PI)-binding modules that target proteins to membrane surfaces. Here we define a family of PH domain proteins, including Tiam1 and ArhGAP9, that demonstrates specificity for PI(4,5)P2, as well as for PI(3,4,5)P3 and PI(3,4)P2, the products of PI 3-kinase. These PH domain family members utilize a non-canonical phosphoinositide binding pocket related to that employed by β-spectrin. Crystal structures of the PH domain of ArhGAP9 in complex with the headgroups of Ins(1,3,4)P3, Ins(1,4,5)P3, and Ins(1,3,5)P3 reveal how two adjacent phosphate positions in PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 are accommodated through flipped conformations of the bound phospholipid. We validate the non-canonical site of phosphoinositide interaction by showing that binding pocket mutations, which disrupt phosphoinositide binding in vitro, also disrupt membrane localization of Tiam1 in cells. We posit that the diversity in PI interaction modes displayed by PH domains contributes to their versatility of use in biological systems. Pleckstrin homology (PH) domains are phosphoinositide (PI)-binding modules that target proteins to membrane surfaces. Here we define a family of PH domain proteins, including Tiam1 and ArhGAP9, that demonstrates specificity for PI(4,5)P2, as well as for PI(3,4,5)P3 and PI(3,4)P2, the products of PI 3-kinase. These PH domain family members utilize a non-canonical phosphoinositide binding pocket related to that employed by β-spectrin. Crystal structures of the PH domain of ArhGAP9 in complex with the headgroups of Ins(1,3,4)P3, Ins(1,4,5)P3, and Ins(1,3,5)P3 reveal how two adjacent phosphate positions in PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 are accommodated through flipped conformations of the bound phospholipid. We validate the non-canonical site of phosphoinositide interaction by showing that binding pocket mutations, which disrupt phosphoinositide binding in vitro, also disrupt membrane localization of Tiam1 in cells. We posit that the diversity in PI interaction modes displayed by PH domains contributes to their versatility of use in biological systems. The spatial and temporal regulation of protein localization plays an important role in the transduction of signals between sub-cellular compartments. Targeting of proteins to membrane surfaces through interactions with phosphoinositides (PIs) 4The abbreviations used are: PI, phosphoinositide; PH, pleckstrin homology; PLC, phospholipase C; PHn, N-terminal PH domain; GFP, green fluorescent protein; aa, amino acid(s); GST, glutathione S-transferase; MBP, maltose-binding protein; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate; Ins(1,3,4)P3, inositol 1,3,4-trisphosphate; Ins(1,3,5)P3, inositol 1,3,5-trisphosphate; Ins(1,3,4,5)P4, inositol 1,3,4,5-tetraphosphate; PI(3,4)P2, phosphoinositide 3,4-bisphosphate; PI(4,5)P2, phosphoinositide 4,5-bisphosphate; PI(3,4,5)P3, phosphoinositide 3,4,5-trisphosphate; r.m.s.d., root mean square deviation; APS, advanced photon source. promotes the formation of functional complexes and concomitantly restricts their site of biochemical activity (1Di Paolo G. De Camilli P. Nature. 2006; 443: 651-657Crossref PubMed Scopus (2163) Google Scholar). Phosphoinositides are lipid components of cellular membranes that function as signaling molecules. The inositol headgroups of phosphoinositides are differentially phosphorylated, and selectively bound by a variety of protein modules, including PH, FERM, ENTH, FYVE, and PX domains (2DiNitto J. Cronin T. Lambright D. Sci. STKE 2003. 2003; : RE16Google Scholar, 3Balla T. J. Cell Sci. 2005; 118: 2093-2104Crossref PubMed Scopus (213) Google Scholar, 4Lemmon M. Traffic. 2003; 4: 201-213Crossref PubMed Scopus (493) Google Scholar). PH domains were the first phosphoinositide binding domain identified (5Harlan J. Hadjuk P. Yoon H. Fesik S. Nature. 1994; 371: 168-170Crossref PubMed Scopus (687) Google Scholar) and serve important roles in kinase signaling and cytoskeletal organization (6Lemmon M. Ferguson K. Biochem. J. 2000; 350: 1-18Crossref PubMed Scopus (620) Google Scholar, 7Lemmon M. Ferguson K. Abrams C. FEBS Lett. 2002; 513: 71-76Crossref PubMed Scopus (220) Google Scholar). PH domains consist of 100-120 amino acids that form a seven-stranded β-sandwich with a C-terminal α-helix. The PI binding properties of PH domains are diverse, ranging from family members that display no detectable interaction to domains that bind one or more headgroups with nanomolar binding affinity (8Yu J.W. Mendrola J.M. Audhya A. Singh S. Keleti D. De Wald D.B. Murray D. Emr S.D. Lemmon M.A. Mol. Cell. 2004; 13: 677-688Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 9Cozier G. Carlton J. Bouyoucef D. Cullen P. Curr. Top Microbiol. Immunol. 2004; 282: 49-88PubMed Google Scholar, 10DiNitto J. Lambright D. Biochim. Biophys. Acta. 2006; 1761: 850-867Crossref PubMed Scopus (133) Google Scholar). Generally, PH domains that possess weak affinity for phosphoinositides are inefficient at PI-dependent membrane localization. These PH domains may require multimerization or cooperation with other factors for their targeting function (11Maffucci T. Falasca M. FEBS Lett. 2001; 506: 173-179Crossref PubMed Scopus (111) Google Scholar, 12Carlton J. Cullen P. Trends Cell Biol. 2005; 15: 540-547Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). In contrast, PH domains that bind with high affinity and selectivity to either PI(4,5)P2 or the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2 are efficiently targeted to membrane surfaces. The PH domain of PLCδ is a specific sensor of PI(4,5)P2, whereas those of Akt, Btk, and Grp1 exemplify domains that selectively bind with high affinity to PI(3,4)P2 and/or PI(3,4,5)P3 (10DiNitto J. Lambright D. Biochim. Biophys. Acta. 2006; 1761: 850-867Crossref PubMed Scopus (133) Google Scholar). A basic consensus motif within the β1-β2 loop region is characteristic of PH domains that bind phosphoinositides with high affinity and specificity (13Isakoff S. Cardozo T. Andreev J. Li Z. Ferguson K. Abagyan R. Lemmon M. Aronheim A. Skolnik E. EMBO J. 1998; 17: 5374-5387Crossref PubMed Scopus (286) Google Scholar). This motif defines the core of the canonical PI binding pocket, and mutations therein disrupt both phosphoinositide binding and membrane localization functions (14Lemmon M. Ferguson K. Biochem. Soc. Trans. 2001; 29: 377-384Crossref PubMed Scopus (87) Google Scholar). To date, eight protein crystal structures of PI-bound PH domains demonstrate direct interactions between phosphates on the inositol ring and residues of this phosphoinositide recognition motif (15Lietzke S. Bose S. Cronin T. Klarlund J. Chawla A. Czech M. Lambright D. Mol. Cell. 2000; 6: 385-394Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 16Ferguson K. Kavran J. Sankaran V. Fournier E. Isakoff S. Skolnik E. Lemmon M. Mol. Cell. 2000; 6: 373-384Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 17Komander D. Fairservice A. Deak M. Kular G. Prescott A. Downes C. Safrany S. Alessi D. van Aalten D. EMBO J. 2004; 23: 3918-3928Crossref PubMed Scopus (148) Google Scholar, 18Thomas C.C. Deak M. Alessi D.R. van Aalten D.M.F. Curr. Biol. 2002; 12: 1256-1262Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 19Cronin T. DiNitto J. Czech M. Lambright D. EMBO J. 2004; 23: 3711-3720Crossref PubMed Scopus (84) Google Scholar, 20Baraldi E. Carugo K.D. Hyvonen M. Lo Surdo P. Riley A.M. Potter B.V.L. Ronan O.B. Ladbury J.E. Saraste M. Structure. 1999; 7: 449-460Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 21Ferguson K. Lemmon M. Schlessinger J. Sigler P. Cell. 1995; 83: 1037-1046Abstract Full Text PDF PubMed Scopus (543) Google Scholar). Additional interactions with the bound phosphoinositide are contributed by more variable regions of the PH domain, including residues within the β3-β4 and β6-β7 loop regions. This PI-recognition motif has facilitated identification of additional PH domain containing proteins that bind phosphoinositides within the canonical binding pocket (22Dowler S. Currie R. Campbell D. Deak M. Kular G. Downes C. Alessi D. Biochem. J. 2000; 351: 19-31Crossref PubMed Scopus (482) Google Scholar). Despite its power in predicting PI-binding properties, the conventional phosphoinositide recognition motif is not apparent in proteins as Tiam1 that require a functional PH domain for membrane localization J. P. van R. C. J. J. Cell Biol. PubMed Scopus Google Scholar). Tiam1 is a protein in of the A. R. J. FEBS Lett. 2003; PubMed Scopus Google Scholar). The C-terminal region of Tiam1 a region with activity specific for G. J. van R. J. Nature. 1995; PubMed Scopus Google Scholar). In contrast, the N-terminal PH domain of Tiam1 is for localization to the membrane through its apparent binding for PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 J. P. van R. C. J. J. Cell Biol. PubMed Scopus Google Scholar, A. K. A. G. A. Czech M. K. S. D. C. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Downes C. Biochem. J. 2000; 351: PubMed Scopus Google Scholar). The PI-binding displayed by with the of characteristic of PH domains that bind phosphoinositides with high affinity and a of Here we that the PH domain of Tiam1 is of a of PH domains that lipid binding and bind phosphoinositides through a non-canonical related to that employed by the PH domain of β-spectrin. of one the ArhGAP9 PH domain, that its PI-binding properties are by the to in flipped and in the were from Downes mutations of and within the domain were by and by The and of and Tiam1 were and for The PH domain of The PH domain of ArhGAP9 by from and and of were by and by and PH protein in by of to at for at Cell were in and in the of and to a with The PH domain from by with at in by on and containing the PH domain were to and at The maltose-binding protein proteins PHn, and and were as the to proteins were with and by a in and and at were by a The phosphoinositide possess with a fluorescent through the of one to the on the inositol ring of protein were to fluorescent phosphoinositide in containing and at of were at a were that the and for the and from a of were the Tiam1 were in with at and were in a and with and were in were a were of and at and were in and were with by a The proteins were and of the PH domain were by in by of a containing protein and Ins(1,4,5)P3, Ins(1,3,4)P3, or Ins(1,3,5)P3 with of a containing of bound to inositol within and were in of in the with of a from a crystal in a at to at and Z. PubMed Scopus Google Scholar). and of a to at and J. Scopus Google Scholar). of with of a to at and and for ArhGAP9 PH in are for in the in are for in the is the of the of and is the for in are for in the and for the and of regions regions regions in are for in the is the of the of and is the for and for the and of in a The complex by with an of PH domain structures of P. S. H. D. G. Structure. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar) as a and the Biol. 2005; PubMed Scopus Google Scholar). Top for and functions a that were to an of and of the The and through with and A. P. G. P. R. J. J. M. R. T. G. D. Biol. 1998; PubMed Scopus Google Scholar, A. J. S. M. A. PubMed Scopus Google Scholar). The and complexes were by the by and with and Biol. 1994; PubMed Scopus Google Scholar, P. K. D. Biol. 2004; PubMed Scopus Google Scholar). for are in Tiam1 a of the PI-binding specificity of the Tiam1 PH domain, we the affinity of its N-terminal PH domain a of phosphoinositide a region of Tiam1 C-terminal to PHn, is for membrane targeting in J. E. van H. van R. J. J. Biol. Full Text Full Text PDF PubMed Scopus (133) Google we also the PI-binding specificity of a PH domain this the domain of Tiam1 and an including the PH domain and adjacent region were in E. as and for PI binding a we employed phosphoinositides with to the fluorescent for in and in Tiam1 and bound phosphoinositides with a for PI(3,4,5)P3, PI(3,4)P2, and displayed binding for and for inositol not displayed affinity for phosphoinositides for as with This may the that the domain is to The of the Tiam1 domain for PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 other as in is in with lipid A. Downes C. Biochem. J. 2000; 351: PubMed Scopus Google Scholar). also that both Tiam1 displayed a for PI(3,4,5)P3 PI(4,5)P2 and This PI binding is from that of the PH domain, which a well for PI(3,4,5)P3 and PI(3,4)P2 and and from the PH domain of which PI(4,5)P2 (10DiNitto J. Lambright D. Biochim. Biophys. Acta. 2006; 1761: 850-867Crossref PubMed Scopus (133) Google Scholar). We that the PI binding of Tiam1 a of the PH domain or the use of an PI-binding of PH domain for protein S.D. S.D. S.D. S.D. S.D. S.D. in a Tiam1 to a of PH that Tiam1 the β1-β2 characteristic of high affinity binding PH domains as Akt, Btk, and PLCδ (13Isakoff S. Cardozo T. Andreev J. Li Z. Ferguson K. Abagyan R. Lemmon M. Aronheim A. Skolnik E. EMBO J. 1998; 17: 5374-5387Crossref PubMed Scopus (286) Google Scholar). of residues identified in a crystal of the PH domain in complex with the inositol of PI(4,5)P2 M. M. M. H. Saraste M. M. EMBO J. 1995; PubMed Scopus Google Scholar). The PH domain of a non-canonical PI-binding by two and within the β1-β2 and loop To date, no other PH domain has to bind phosphoinositides a To a binding pocket within the Tiam1 domain is for its to bind both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2, we residues within Tiam1 and their on PI-binding We both and with within the β1-β2 loop region of Tiam1 for this A form of the Tiam1 region and PI-binding activity with the a to in binding affinity for phosphoinositide and by at the as Tiam1 the protein not To the of binding pocket mutations on Tiam1 membrane localization in the in the of of and Tiam1 were for membrane localization in cells. that the domain and membrane localization in also as a localization A. Downes C. Biochem. J. 2000; 351: PubMed Scopus Google Scholar). at the between with and A. Downes C. Biochem. J. 2000; 351: PubMed Scopus Google Scholar, J. E. P. J. Biochem. J. 2006; PubMed Scopus Google of the domain of Tiam1 in with and with a of PI-binding the within the the of by the mutations not to Tiam1 In the PH that a of the to as Tiam1 and proteins were to as by These the Tiam1 PH domain may functions as a direct interaction with the complex J. E. P. J. Biochem. J. 2006; PubMed Scopus Google Scholar). on we that a binding pocket of Tiam1 is for high affinity and phosphoinositide binding and for the localization of the Tiam1 protein in cells. PH of S. T. A. J. Z. D. PubMed Scopus Google we identified of PH domains with to the Tiam1 PH domain and with of the residues in These the PH domains of and We to as PH domains We that additional PH domains display PI-binding as for To this we first ArhGAP9 a protein containing PH, and domains T. T. H. M. J. Biochem. Biophys. 2001; PubMed Scopus Google Scholar). The PH domain of is one of the members of the and we that its PI-binding properties reveal members of the are The PH domain of as an and for PI-binding The PH domain bound to PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 with and and In contrast, bound to or PI with affinity for The that and Tiam1 PH domains display PI-binding the that the of PH domains may a related We that members may use a pocket to bind PI(3,4,5)P3, PI(3,4)P2, and the of the PH domain of has in complex with PI(4,5)P2, the by which the non-canonical PH domain pocket selectively and phosphoinositide to of PH domain for in a of PH the by which the of PH domains both PI(4,5)P2 and the PI 3-kinase products PI(3,4)P2 and PI(3,4,5)P3, we the PH domains of Tiam1 and for in the of Ins(1,3,4,5)P4, Ins(1,3,4)P3, and Ins(1,4,5)P3, which to the headgroups of PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2, for to Tiam1 were protein of in complex with two high affinity and with the affinity were of in complex with as to The by an of homology from the PH P. S. H. D. G. Structure. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The of residues that a PH domain with and a C-terminal α-helix. The β3-β4 loop of residues to and not in the and for structures in this are in The of bound within a pocket that is from the canonical pocket by Akt, and related PH domains for within the between the β1-β2 and loop regions of the PH domain The of interaction between and on the phosphate of the inositol The phosphate is by the of and the of and one with the of The phosphate is and one interaction to and a to the of The phosphate is by two interactions to the of and two interactions to In phosphate of is by with a of interactions on the phosphate of PH domain binding to and Ins(1,3,5)P3 to of bound is as a at residues are as with by positions of the inositol ring are are by In a phosphate of the Ins(1,3,5)P3 is The is to that of mean square of and the two PH domains bind through a binding pocket A and the in two from in how the PI(4,5)P2 the of bound is the in both PH domain the of the inositol ring within the pocket is the loop region of This in the and of the residues that the phosphate and in the loop region of are the of and of A that may for the in the inositol ring the binding pocket that both and phosphates on This in is contributed by whereas the in is contributed by the β1-β2 loop The of is to the loop region that of both residues with the adjacent and phosphates of their we that and utilize a related of interactions and binding residues to how a pocket PI 3-kinase phosphoinositide we the PH domain in complex with as The of at by the PH domain as a The of residues and a well β3-β4 loop region containing a that in the in for the within the β1-β2 and binding pocket The between and structures is the of the bound phosphoinositide The inositol of the two complexes are related by an the a of the flipped ring of is in a binding pocket as of Despite the flipped the phosphate to both phosphoinositides the of PH domain with a of interactions in the and interactions between and of by the of and and an interaction with In the phosphate in is by the of as the for the the phosphate in is and one to the of In to the the phosphate additional interactions with the of and In to a flipped of the inositol the bound in the complex the of as with This a direct interaction between the of and the of In the of is to with In the and are also by and This phosphoinositide is accommodated by and may serve to the interactions between and the of to PH we were to the PH domain with the high affinity PI(3,4,5)P3, we to its binding on the and To which flipped of the bound inositol ring we the phosphoinositide of PI(3,4,5)P3 the and positions In both the phosphate to accommodated In the the additional phosphate the binding pocket within direct or to the of In the the additional phosphate the binding pocket, is within to the of The of and the to form additional with the phosphoinositide binding pocket of that accommodated by either of the two binding This is with that binding affinity for PI(3,4,5)P3 is to the affinity for PI(4,5)P2 and PI(3,4)P2 PH domain in complex with a affinity Ins(1,3,5)P3 as with the as These to The by the within the β1-β2 and phosphoinositide binding pocket not for by a binding for the Ins(1,3,5)P3 apparent for a phosphate to the in the phosphoinositide We not which phosphate of Ins(1,3,5)P3 this site in the The phosphate a of interactions with the of and the residues that the in the and is apparent for regions the to the the additional by the or the phosphate binding site of the Ins(1,3,5)P3 by to the inositol in the and the other phosphate of the inositol ring to the other in the binding The of to of the phosphate interaction for the of this in the crystal and its weak binding affinity for with the of for the the of that with the phosphate in the and structures is also We posit that the of two adjacent phosphate positions and or and on the inositol ring of PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2, which is in is a of high affinity phosphoinositide binding to the family of PH of PI validate the phosphoinositide interactions in the PH domain residues within the binding pocket of were to and for PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 were the of in protein that and not not of the other proteins were well and binding affinity for PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 to the PH The of mutations from an for the to for the The of the by the that the of with both of the two adjacent phosphates of the inositol ring of and of The in binding for the binding affinity for to a to phosphoinositide binding by The of the by the that this a interaction to a phosphate that is by additional binding pocket a the to a within the β1-β2 loop region of PH the PI binding pocket, no on binding affinity for PI(3,4,5)P3 or of the PH domain interaction with PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 by and The for this of the on phosphoinositide binding from and may A of PH that the PH domain of ArhGAP9 a non-canonical phosphoinositide binding that to a PI binding a for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and The binding is not a of that employed by the of high affinity phosphoinositide binding PH a of the M. M. M. H. Saraste M. M. EMBO J. 1995; PubMed Scopus Google Scholar). binding and that the ArhGAP9 lipid binding is also employed by the PH domain of of the ArhGAP9 PH domain in complex with and the use of a non-canonical pocket and the for specific and high affinity binding to PI(3,4)P2 and we also binding modes of PI(3,4,5)P3 to the PH domain of The non-canonical PI binding pocket of is which the and phosphate of This with the canonical PI-binding for the of PH the and positions of the inositol ring are The of the non-canonical binding pocket contributes to its to both PI(3,4)P2 and PI(4,5)P2 two related by a the of the inositol that and Tiam1 to a PH domain family that may lipid binding and phosphoinositides through a a of the PH and PH domains utilize the β1-β2 and binding pocket for phosphoinositide the of the bound and the of interactions and of pocket residues between the two domains The of interactions between the inositol phosphates and non-canonical binding pocket is more in This may for the affinity of for displayed by and one in that is within the binding pocket and phosphoinositide in the This with the PH domains that a canonical binding pocket for phosphoinositide which basic residues within an motif (13Isakoff S. Cardozo T. Andreev J. Li Z. Ferguson K. Abagyan R. Lemmon M. Aronheim A. Skolnik E. EMBO J. 1998; 17: 5374-5387Crossref PubMed Scopus (286) Google Scholar). the PH domain of also bind to the PI 3-kinase products PI(3,4,5)P3 and A of the PI-binding specificity for to binding that the PH domain of bind not A. K. A. G. A. Czech M. K. S. D. C. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. M. H. Saraste M. M. EMBO J. 1995; PubMed Scopus Google Scholar). The functional of to the PH domains a more of PI-binding of the PH binding of phosphoinositide products to the interaction domain through flipped conformations of the inositol ring has not a in binding has the of two phosphoinositides bound to two PH domains (6Lemmon M. Ferguson K. Biochem. J. 2000; 350: 1-18Crossref PubMed Scopus (620) Google Scholar). PLCδ and PH domains bind and Ins(1,3,4,5)P4, of their inositol for the flipped of phosphoinositide headgroups are related through a the of the inositol the in the canonical pocket of PLCδ and domain from both and within the This PLCδ and PH domains not efficiently bind PI(3,4)P2 and PI(4,5)P2 flipped inositol ring not within the of a canonical PI binding pocket, related to the of the inositol of the PH domain in complex with and two related by a T. DiNitto J. Czech M. Lambright D. EMBO J. 2004; 23: 3711-3720Crossref PubMed Scopus (84) Google Scholar). This phosphate of the inositol ring in binding pocket the and of PI(4,5)P2 in the and binding of the PI(3,4,5)P3 (10DiNitto J. Lambright D. Biochim. Biophys. Acta. 2006; 1761: 850-867Crossref PubMed Scopus (133) Google Scholar). both inositol ring within the non-canonical PI binding pocket and inositol ring within canonical PI binding pocket the to the of phosphoinositide specificity displayed by PH of the β1-β2 and that the non-canonical binding pocket by the β1-β2 and loop regions is employed by PH domains the family we define in this The domain, and domain possess a PH homology to PH and display of phosphoinositide binding within the binding pocket H. D. J. D. Emr S. R. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, P. T. K. M. P. J. 2005; PubMed Scopus Google Scholar, P. H. H. J. M. S. Structure. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. J. J. C. T. H. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). domains the residues in or This that more in the by which PH domains phosphoinositides within the non-canonical binding pocket to on the that specific functions as for canonical PH as we for PH to function for the PH domains in the The PH domains of proteins as PLCδ and Grp1 bind a specific PI(4,5)P2 and PI(3,4,5)P3, in a that with their biological PLCδ is targeted to regions of the membrane in its whereas Grp1 as a target of PI 3-kinase this high of phosphoinositide binding selectivity for PH domains may the the (6Lemmon M. Ferguson K. Biochem. J. 2000; 350: 1-18Crossref PubMed Scopus (620) Google Scholar). The PI-binding properties of the Tiam1 and PH from use of the non-canonical binding pocket, may to signals to their family this the Tiam1 to a by binding to PI(4,5)P2, which in to signals that PI(3,4,5)P3 and In both and the function of Tiam1 is by its localization to specific and to and cellular organization A. T. C. van R. J. J. Cell Biol. 2005; PubMed Scopus Google Scholar, H. Cell Biol. 2006; PubMed Scopus Google Scholar). This is by properties of the Tiam1 which is at of the non-canonical PI-binding to reveal functions in to phosphoinositide binding for this of PH We S. H. of for the ArhGAP9 and Downes for the and We and the of at the of for with with

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