PDBsum entry 1fhw

Signaling protein

PDB id: 1fhw

Contents

Protein chains

122 a.a. *

Ligands

I5P ×2

SO4

Waters ×164

* Residue conservation analysis

PDB id:

1fhw

Name:

Signaling protein

Title:

Structure of the pleckstrin homology domain from grp1 in complex with inositol(1,3,4,5,6)pentakisphosphate

Structure:

Guanine nucleotide exchange factor and integrin binding protein homolog grp1. Chain: a, b. Fragment: pleckstrin homology domain. Synonym: grp1. Engineered: yes. Other_details: complex with inositol (1,3,4,5,6)-pentakisphosphate

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.90Å R-factor: 0.229 R-free: 0.270

Authors:

K.M.Ferguson,J.M.Kavran,V.G.Sankaran,E.Fournier,S.J.Isakoff, E.Y.Skolnik,M.A.Lemmon

Key ref:

K.M.Ferguson et al. (2000). Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains. Mol Cell, 6, 373-384. PubMed id: 10983984 DOI: 10.1016/S1097-2765(00)00037-X

Date:

02-Aug-00 Release date: 23-Aug-00

Protein chains

O08967  (CYH3_MOUSE) -  Cytohesin-3 from Mus musculus

Seq: 399 a.a.

Struc: 122 a.a.

DOI no: 10.1016/S1097-2765(00)00037-X

Mol Cell 6:373-384 (2000)

PubMed id: 10983984

Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.

K.M.Ferguson, J.M.Kavran, V.G.Sankaran, E.Fournier, S.J.Isakoff, E.Y.Skolnik, M.A.Lemmon.

ABSTRACT

Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns(3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.

Selected figure(s)

Figure 1.
Figure 1. DAPP1-PH and Grp1-PH Recognize Distinct Patterns of Phosphate Groups(A) Binding of Ins(1,3,4)P[3] (magenta, squares), and Ins(1,5,6)P[3] (which has the same phosphate arrangement as Ins(3,4,5)P[3]) (cyan, triangles) to DAPP1-PH (left) and Grp1-PH (right) is compared using a ^3H-Ins(1,3,4,5)P[4] competition assay ([17]). DAPP1-PH binds 10-fold more strongly to Ins(1,3,4)P[3] than to the Ins(3,4,5)P[3] analog, while the converse is true for Grp1-PH.(B) Structures of the inositol trisphosphates. Ins(1,3,4)P[3] (magenta) and Ins(3,4,5)P[3] (cyan) are compared. Note that Ins(3,4,5)P[3] is equivalent to Ins(1,5,6)P[3] except in the positioning of the single axial hydroxyl group (2-OH). Ins(3,4,5)P[3] is not commercially available, so Ins(1,5,6)P[3] was used for the experiment shown in (A). Since Ins(3,5,6)P[3] and Ins(1,3,4)P[3] bind identically to DAPP1-PH (Table 1), we suggest that the axial 2-hydroxyl is not likely to be important in defining binding specificity.

Figure 6.
Figure 6. Prediction of PH Domain 3-Phosphoinositide SpecificityPH domains shown to recognize PI 3-kinase products ([15]) are aligned with Grp1-PH and Btk-PH (A) or DAPP1-PH (B), according to whether they are predicted (see text) to make direct side chain contacts with the 5-phosphate of Ins(1,3,4,5)P[4]. Elements of secondary structure are delineated with gray arrows (β strands) or a black bar (the C-terminal α helix). Residues are colored when their side chain is involved in interactions with Ins(1,3,4,5)P[4] in the Btk-PH, Grp1-PH, or DAPP1-PH complex structures. Yellow represents interaction with the 1-phosphate; red, the 3-phosphate; green, the 4-phosphate; and blue, the 5-phosphate. Color coding is predicted for PH domains of unknown structure. The 3-phosphoinositide binding motif ([15]) in the β1/β2 region is also color coded as described above. In (A), PH domains with names underlined are known to select PtdIns(3,4,5)P[3] over PtdIns(3,4)P[2]. Others are predicted to do so. In (B), DAPP1-PH and PKB-PH are both known to bind almost equally to PtdIns(3,4,5)P[3] and PtdIns(3,4)P[2]. Others are predicted to do so.

The above figures are reprinted by permission from Cell Press: Mol Cell (2000, 6, 373-384) copyright 2000.

Figures were selected by an automated process.