1EAZ

Crystal structure of the phosphoinositol (3,4)-bisphosphate binding PH domain of TAPP1 from human.

Summary for 1EAZ

• Entry DOI: 10.2210/pdb1eaz/pdb
• Descriptor: TANDEM PH DOMAIN CONTAINING PROTEIN-1, CITRIC ACID (3 entities in total)
• Functional Keywords: lipid-binding protein, lipid degradation, ph domain, phosphatidylinositol (3, 4)-bisphosphate, signalling, lipid binding protein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 14432.43

Authors

Thomas, C.C.,Dowler, S.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2001-07-17, release date: 2002-07-11, Last modification date: 2023-12-13)

Primary citation

Thomas, C.C.,Dowler, S.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F.
Crystal Structure of the Phosphatidylinositol 3,4-Bisphosphate-Binding Pleckstrin Homology (Ph) Domain of Tandem Ph-Domain-Containing Protein 1 (Tapp1): Molecular Basis of Lipid Specificity
Biochem.J., 358:287-, 2001

PubMed Abstract: Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] and its immediate breakdown product PtdIns(3,4)P(2) function as second messengers in growth factor- and insulin-induced signalling pathways. One of the ways that these 3-phosphoinositides are known to regulate downstream signalling events is by attracting proteins that possess specific PtdIns-binding pleckstrin homology (PH) domains to the plasma membrane. Many of these proteins, such as protein kinase B, phosphoinositide-dependent kinase 1 and the dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1) interact with both PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) with similar affinity. Recently, a new PH-domain-containing protein, termed tandem PH-domain-containing protein (TAPP) 1, was described which is the first protein reported to bind PtdIns(3,4)P(2) specifically. Here we describe the crystal structure of the PtdIns(3,4)P(2)-binding PH domain of TAPP1 at 1.4 A (1 A=0.1 nm) resolution in complex with an ordered citrate molecule. The structure is similar to the known structure of the PH domain of DAPP1 around the D-3 and D-4 inositol-phosphate-binding sites. However, a glycine residue adjacent to the D-5 inositol-phosphate-binding site in DAPP1 is substituted for a larger alanine residue in TAPP1, which also induces a conformational change in the neighbouring residues. We show that mutation of this glycine to alanine in DAPP1 converts DAPP1 into a TAPP1-like PH domain that only interacts with PtdIns(3,4)P(2), whereas the alanine to glycine mutation in TAPP1 permits the TAPP1 PH domain to interact with PtdIns(3,4,5)P(3).

PubMed: 11513726
DOI: 10.1042/0264-6021:3580287

Experimental method

X-RAY DIFFRACTION (1.4 Å)