The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain.
Amyloid beta-peptide, which forms neuronal and vascular amyloid deposits in Alzheimer's disease, is derived from an integral membrane protein precursor. The biological function of the precursor is currently unclear. Here we describe the X-ray structure of E2, the largest of the three conserved domains of the precursor. The structure of E2 consists of two coiled-coil substructures connected through a continuous helix and bears an unexpected resemblance to the spectrin family of protein structures. E2 can reversibly dimerize in the solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. Heparan sulfate proteoglycans, the putative ligand for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.
Wang
Yongcheng
Y
Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Ha
Ya
Y
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D014961:X-Ray Diffraction
D016564:Amyloid beta-Protein Precursor