PDBsum entry 2p0h

Ligand binding protein

PDB id

2p0h

Loading ...

Contents

			Protein chain

					118 a.a. *

			Ligands

					I3S

			Waters ×72

* Residue conservation analysis

PDB id:

2p0h

Links

Name:

Ligand binding protein

Title:

Arhgap9 ph domain in complex with ins(1,3,4)p3

Structure:

Rho gtpase-activating protein 9. Chain: a. Fragment: pleckstrin homology domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: arhgap9. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å

R-factor:

0.197

R-free:

0.246

Authors:

D.F.J.Ceccarelli,I.Blasutig,M.Goudreault,J.Ruston,T.Pawson,F.Sicheri

Key ref:

D.F.Ceccarelli et al. (2007). Non-canonical interaction of phosphoinositides with pleckstrin homology domains of Tiam1 and ArhGAP9. J Biol Chem, 282, 13864-13874. PubMed id: 17339315 DOI: 10.1074/jbc.M700505200

Date:

28-Feb-07

Release date:

27-Mar-07

PROCHECK

	Headers

	References

Protein chain

Q9BRR9 (RHG09_HUMAN) - Rho GTPase-activating protein 9 from Homo sapiens

Seq: Struc:

Seq: Struc:					750 a.a. 118 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

DOI no: 10.1074/jbc.M700505200	J Biol Chem 282:13864-13874 (2007)
PubMed id: 17339315

Non-canonical interaction of phosphoinositides with pleckstrin homology domains of Tiam1 and ArhGAP9.
D.F.Ceccarelli, I.M.Blasutig, M.Goudreault, Z.Li, J.Ruston, T.Pawson, F.Sicheri.

ABSTRACT

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)P(2), as well as for PI(3,4,5)P(3) and PI(3,4)P(2), the products of PI 3-kinase. These PH domain family members utilize a non-canonical phosphoinositide binding pocket related to that employed by beta-spectrin. Crystal structures of the PH domain of ArhGAP9 in complex with the headgroups of Ins(1,3,4)P(3), Ins(1,4,5)P(3), and Ins(1,3,5)P(3) reveal how two adjacent phosphate positions in PI(3,4)P(2), PI(4,5)P(2), and PI(3,4,5)P(3) 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.

Selected figure(s)



	Figure 7. FIGURE 7. Stereographic view of AG9 PH domain binding to Ins(1,4,5)P[3] (A), Ins(1,3,4)P[3] (B), and Ins(1,3,5)P[3] (C). Experimental F[o] - F[c] electron density map prior to modeling of bound ligand is shown as a wire mesh contoured at 2.5 sigma. PI-interacting residues are shown as stick models with hydrogen bonds indicated by dashed lines. Phosphate positions of the inositol ring are labeled. Water molecules are indicated by red spheres. In C only a single phosphate moiety of the Ins(1,3,5)P3 ligand is modeled.		Figure 8. FIGURE 8. Superimposed stereographic view of the AG9^145 and AG9^134 PI binding pockets in complex with Ins(1,4,5)P[3] and Ins(1,3,4)P[3], respectively. The PH domain of AG9^145 is colored cyan with bound Ins(1,4,5)P[3] in purple; the AG9^134 PH domain is colored green with bound Ins(1,3,4)P[3] in pink. Orientation of bound PI(4,5)P[2] and PI(3,4)P[2] are related by a rotation of 180° about the P1-P4 axis of the inositol ring.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21418524

P.Schläfli, J.Tröger, K.Eckhardt, E.Borter, P.Spielmann, and R.H.Wenger (2011).
Substrate preference and phosphatidylinositol monophosphate inhibition of the catalytic domain of the Per-Arnt-Sim domain kinase PASKIN.

FEBS J, 278, 1757-1768.

20357244

A.McDowall, L.Svensson, P.Stanley, I.Patzak, P.Chakravarty, K.Howarth, H.Sabnis, M.Briones, and N.Hogg (2010).
Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro.

Blood, 115, 4834-4842.

21119626

O.Gallego, M.J.Betts, J.Gvozdenovic-Jeremic, K.Maeda, C.Matetzki, C.Aguilar-Gurrieri, P.Beltran-Alvarez, S.Bonn, C.Fernández-Tornero, L.J.Jensen, M.Kuhn, J.Trott, V.Rybin, C.W.Müller, P.Bork, M.Kaksonen, R.B.Russell, and A.C.Gavin (2010).
A systematic screen for protein-lipid interactions in Saccharomyces cerevisiae.

Mol Syst Biol, 6, 430.

PDB code:

3nsu

19893486

S.Terawaki, K.Kitano, T.Mori, Y.Zhai, Y.Higuchi, N.Itoh, T.Watanabe, K.Kaibuchi, and T.Hakoshima (2010).
The PHCCEx domain of Tiam1/2 is a novel protein- and membrane-binding module.

EMBO J, 29, 236-250.

PDB codes:

3a8n 3a8p 3a8q

20559318

T.G.Kutateladze (2010).
Translation of the phosphoinositide code by PI effectors.

Nat Chem Biol, 6, 507-513.

20943760

Y.H.Huang, and K.Sauer (2010).
Lipid signaling in T-cell development and function.

Cold Spring Harb Perspect Biol, 2, a002428.

19648926

R.S.Depetris, J.Wu, and S.R.Hubbard (2009).
Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14.

Nat Struct Mol Biol, 16, 833-839.

PDB code:

3hk0

19008549

R.V.Stahelin (2009).
Lipid binding domains: more than simple lipid effectors.

J Lipid Res, 50, S299-S304.

18273061

C.Ng, R.A.Jackson, J.P.Buschdorf, Q.Sun, G.R.Guy, and J.Sivaraman (2008).
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.

EMBO J, 27, 804-816.

PDB codes:

3bum 3bun 3buo 3buw 3bux

18768751

D.Komander, M.Patel, M.Laurin, N.Fradet, A.Pelletier, D.Barford, and J.F.Côté (2008).
An alpha-helical extension of the ELMO1 pleckstrin homology domain mediates direct interaction to DOCK180 and is critical in Rac signaling.

Mol Biol Cell, 19, 4837-4851.

PDB code:

2vsz

18765636

H.L.Ma, T.Zhang, J.Meng, Z.Y.Qin, F.Du, Q.Y.Wang, and S.L.Wei (2008).
The role of T-lymphoma invasion and metastasis inducing protein 1 in early pregnancy in mice.

Mol Hum Reprod, 14, 589-594.

19026786

K.D.Swanson, Y.Tang, D.F.Ceccarelli, F.Poy, J.P.Sliwa, B.G.Neel, and M.J.Eck (2008).
The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch.

Mol Cell, 32, 564-575.

PDB codes:

1u5g 2otx

18216767

M.A.Lemmon (2008).
Membrane recognition by phospholipid-binding domains.

Nat Rev Mol Cell Biol, 9, 99.

17967873

X.Cai, D.Lietha, D.F.Ceccarelli, A.V.Karginov, Z.Rajfur, K.Jacobson, K.M.Hahn, M.J.Eck, and M.D.Schaller (2008).
Spatial and temporal regulation of focal adhesion kinase activity in living cells.

Mol Cell Biol, 28, 201-214.

18505730

Y.Ugolev, Y.Berdichevsky, C.Weinbaum, and E.Pick (2008).
Dissociation of Rac1(GDP).RhoGDI complexes by the cooperative action of anionic liposomes containing phosphatidylinositol 3,4,5-trisphosphate, Rac guanine nucleotide exchange factor, and GTP.

J Biol Chem, 283, 22257-22271.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.