PDBsum entry 2idh

Protein binding

PDB id: 2idh

Contents

Protein chains

30 a.a. *

31 a.a. *

34 a.a. *

33 a.a. *

Ligands

SO4 ×2

PG4 ×7

Waters ×119

* Residue conservation analysis

PDB id:

2idh

Name:

Protein binding

Title:

Crystal structure of human fe65 ww domain

Structure:

Amyloid beta a4 protein-binding family b member 1. Chain: a, b, c, d, e, f, g, h. Fragment: ww domain. Synonym: fe65 protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: apbb1, fe65. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.28Å R-factor: 0.220 R-free: 0.282

Authors:

M.Meiyappan,G.Birrane,J.A.A.Ladias

Key ref:

M.Meiyappan et al. (2007). Structural Basis for Polyproline Recognition by the FE65 WW Domain. J Mol Biol, 372, 970-980. PubMed id: 17686488 DOI: 10.1016/j.jmb.2007.06.064

Date:

15-Sep-06 Release date: 10-Jul-07

Protein chains

O00213  (APBB1_HUMAN) -  Amyloid beta precursor protein binding family B member 1 from Homo sapiens

Seq: 710 a.a.

Struc: 30 a.a.

Protein chains

O00213  (APBB1_HUMAN) -  Amyloid beta precursor protein binding family B member 1 from Homo sapiens

Seq: 710 a.a.

Struc: 31 a.a.

Protein chain

O00213  (APBB1_HUMAN) -  Amyloid beta precursor protein binding family B member 1 from Homo sapiens

Seq: 710 a.a.

Struc: 34 a.a.*

Protein chain

O00213  (APBB1_HUMAN) -  Amyloid beta precursor protein binding family B member 1 from Homo sapiens

Seq: 710 a.a.

Struc: 33 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2007.06.064

J Mol Biol 372:970-980 (2007)

PubMed id: 17686488

Structural Basis for Polyproline Recognition by the FE65 WW Domain.

M.Meiyappan, G.Birrane, J.A.Ladias.

ABSTRACT

The neuronal protein FE65 functions in brain development and amyloid precursor protein (APP) signaling through its interaction with the mammalian enabled (Mena) protein and APP, respectively. The recognition of short polyproline sequences in Mena by the FE65 WW domain has a central role in axon guidance and neuronal positioning in the developing brain. We have determined the crystal structures of the human FE65 WW domain (residues 253-289) in the apo form and bound to the peptides PPPPPPLPP and PPPPPPPPPL, which correspond to human Mena residues 313-321 and 347-356, respectively. The FE65 WW domain contains two parallel ligand-binding grooves, XP (formed by residues Y269 and W280) and XP2 (formed by Y269 and W271). Both Mena peptides adopt a polyproline helical II conformation and bind to the WW domain in a forward (N-C) orientation through selection of the PPPPP motif by the XP and XP2 grooves. This mode of ligand recognition is strikingly similar to polyproline interaction with SH3 domains. Importantly, comparison of the FE65 WW structures in the apo and liganded forms shows that the XP2 groove is formed by an induced-fit mechanism that involves movements of the W271 and Y269 side-chains upon ligand binding. These structures elucidate the molecular determinants underlying polyproline ligand selection by the FE65 WW domain and provide a framework for the design of small molecules that would interfere with FE65 WW-ligand interaction and modulate neuronal development and APP signaling.

Selected figure(s)

Figure 1.
Figure 1. (a) Sequence comparison of representative WW domains. The sequences of the single WW of FE65, dystrophin, and Pin1, the first WW of FBP11, PRP40, YAP65, and Nedd4, and the second WW of FBP28, were aligned using the program CLUSTAL W.^56 Hyphens represent gaps inserted for optimum alignment. The secondary structure elements of FE65 WW are indicated at the top. Residues of human FE65 are numbered. Two conserved tryptophan residues (after which the domain is named) are shown in white on a blue background. Invariant tyrosine residues (shown in white on a red background) and bulky hydrophobic residues (highlighted in yellow) form the XP2 groove in group II/III domains. Conserved threonine/serine residues that hydrogen bond with the ligand are highlighted in green. (b) Ribbon diagram of the FE65 WW domain. Residues that form the XP and XP2 groves are shown as yellow stick models. The side-chains of residues forming a hydrophobic core that stabilizes the fold are shown in pink. (c) A stereo view of eight FE65 WW molecules present in the asymmetric unit. Superposition of these independent structures shows that they fall into two distinct conformations highlighted in shades of green (apo form) and pink (bound to a PEG400 molecule). Note the conformational changes of the W271 and Y269 side-chains in the bound form. (d) In the apo form, the XP2 groove is shallow. (e) Binding of a PEG400 molecule induces the formation of a deep XP2 groove, primarily through conformational changes of the indole side-chain of W271 and, to a lesser degree, of the phenyl ring of Y269. The Figure was made using PyMol [www.pymol.org].

Figure 4.
Figure 4. (a) Surface representation of the FE65 WW bound to the Mn10 peptide (shown as a stick model). Semitransparent rectangles denote the parallel orientation of the XP and XP2 grooves. (b) A diagram of the FE65 WW bound to Mn10 PPII helix (shown as a triangular prism), illustrating the parallel arrangement of the XP and XP2 grooves, the three aromatic residues that form them, and the proline residues of the ligand that occupy them (orange spheres). Unbound proline and leucine residues are shown as gray and cyan spheres, respectively. (c) Surface representation of the FBP11 WW1 bound to PPLP sequence (PDB code 2DYF), showing the non-parallel arrangement of the XP and XP2 grooves (rectangles). (d) Surface representation of the Abl tyrosine kinase SH3 domain bound to the peptide 3BP1 containing the sequence PPLPP (PDB code 1ABO), showing the parallel XP and XP2 grooves (rectangles). (e) A stereo view of the FE65 WW–Mn10 structure superimposed on the Abl SH3–3BP1 complex, showing the similar mode of PPII recognition by the aromatic triad of WW (yellow) and SH3 (light green) domains. The Mn10 and 3BP1 peptides are shown in cyan and pink, respectively.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2007, 372, 970-980) copyright 2007.

Figures were selected by an automated process.