4PWQ

HIGH-RESOLUTION CRYSTAL STRUCTURE OF THE E1-DOMAIN of THE AMYLOID PRECURSOR PROTEIN

Summary for 4PWQ

• Entry DOI: 10.2210/pdb4pwq/pdb
• Descriptor: Amyloid beta A4 protein (2 entities in total)
• Functional Keywords: heparin binding, dimerization, heparin binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 2
• Total formula weight: 43524.16

Authors

Hoefgen, S.,Dahms, S.O.,Than, M.E. (deposition date: 2014-03-21, release date: 2015-02-04, Last modification date: 2024-10-30)

Primary citation

Hoefgen, S.,Dahms, S.O.,Oertwig, K.,Than, M.E.
The Amyloid Precursor Protein Shows a pH-Dependent Conformational Switch in Its E1 Domain.
J.Mol.Biol., 427:433-442, 2015

PubMed Abstract: The amyloid precursor protein (APP) and its proteolytic cleavage product Aβ are widely believed to be central to the etiology of Alzheimer's disease (AD). APP and its family members are also essential for proper neuronal development and homeostasis. APP is located at the cell surface and within intracellular compartments, cellular regions that exhibit different pH values. The AD-associated amyloidogenic processing of APP is initiated predominantly in intracellular acidic compartments, whereas its non-amyloidogenic cleavage is initiated at the cell surface at slightly basic pH. We analyzed the influence of pH on the APP-E1 domain and found that its two constituting subdomains, GFLD and CuBD, interact with each other in a pH-dependent manner. Dynamic light scattering showed that APP-E1 represents a more open conformation at neutral pH and a more closed conformation at acidic pH. Analyzing a 1.4 Å, high-resolution X-ray structure of E1 derived from merohedrally twinned crystals resulted in the identification of individual residues that are responsible for these pH-dependent interactions. Mutational studies and dynamic light scattering measurements further proved that specific hydrogen bonds between the two carboxylates of D177 and E87, as well as between N89 and H147, are major determinants of this pH-driven conformational switch in APP-E1. These findings show how APP can adopt different conformations depending on pH and suggest that the protein fulfils different functions at distinct localizations within the cell. Additionally, our data suggest a novel strategy for treating AD based on regulating the amyloidogenic processing of APP by the specific interruption of the interaction between the APP-E1 subdomains.

PubMed: 25528641
DOI: 10.1016/j.jmb.2014.12.005

Experimental method

X-RAY DIFFRACTION (1.4 Å)