PDBsum entry: 3dxe

Protein binding

PDB id: 3dxe

Contents

Protein chains

124 a.a. *

27 a.a. *

Waters ×236

* Residue conservation analysis

PDB id:

3dxe

Name:

Protein binding

Title:

Crystal structure of the intracellular domain of human app (t668a mutant) in complex with fe65-ptb2

Structure:

Amyloid beta a4 protein-binding family b member 1. Chain: a, c. Fragment: ptb2 domain, unp residues 534-667. Engineered: yes. Amyloid beta a4 protein. Chain: b, d. Fragment: app intracellular domain, unp residues 739-770. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: apbb1, fe65, rir. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: app, a4, ad1.

Resolution:

2.00Å R-factor: 0.208 R-free: 0.241

Authors:

J.Radzimanowski,I.Sinning,K.Wild

Key ref:

J.Radzimanowski et al. (2008). Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. Embo Rep, 9, 1134-1140. PubMed id: 18833287 DOI: 10.1038/embor.2008.188

Date:

24-Jul-08 Release date: 16-Sep-08

Protein chains

O00213  (APBB1_HUMAN) -  Amyloid beta A4 precursor protein-binding family B member 1

Seq: 710 a.a.

Struc: 124 a.a.

Protein chains

P05067  (A4_HUMAN) -  Amyloid beta A4 protein

Seq: 770 a.a.

Struc: 27 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1038/embor.2008.188

Embo Rep 9:1134-1140 (2008)

PubMed id: 18833287

Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2.

J.Radzimanowski, B.Simon, M.Sattler, K.Beyreuther, I.Sinning, K.Wild.

ABSTRACT

Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (Abeta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and Abeta generation. We determined the crystal structure of the AICD in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T(668), an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T(668) phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.