skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization

Abstract

Amyloid precursor protein (APP) is genetically linked to Alzheimer's disease. APP is a type I membrane protein, and its oligomeric structure is potentially important because this property may play a role in its function or affect the processing of the precursor by the secretases to generate amyloid {beta}-peptide. Several independent studies have shown that APP can form dimers in the cell, but how it dimerizes remains controversial. At least three regions of the precursor, including a centrally located and conserved domain called E2, have been proposed to contribute to dimerization. Here we report two new crystal structures of E2, one from APP and the other from APLP1, a mammalian APP homologue. Comparison with an earlier APP structure, which was determined in a different space group, shows that the E2 domains share a conserved and antiparallel mode of dimerization. Biophysical measurements in solution show that heparin binding induces E2 dimerization. The 2.1 {angstrom} resolution electron density map also reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. The locations of two of these residues, Arg-369 and His-433, at the dimeric interface suggest amore » mechanism for heparin-induced protein dimerization.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
BROOKHAVEN NATIONAL LABORATORY (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1041952
Report Number(s):
BNL-97630-2012-JA
Journal ID: ISSN 0006-2960; BICHAW; TRN: US201212%%363
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Biochemistry (Eaton)
Additional Journal Information:
Journal Volume: 50; Journal Issue: 24; Journal ID: ISSN 0006-2960
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; DIMERIZATION; DIMERS; ELECTRON DENSITY; HEPARIN; MEMBRANE PROTEINS; PHOSPHATES; PRECURSOR; PROCESSING; PROTEINS; RESIDUES; RESOLUTION; SPACE GROUPS

Citation Formats

S Lee, Y Xue, J Hulbert, Y Wang, X Liu, B Demeler, and Y Ha. The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization. United States: N. p., 2011. Web. doi:10.1021/bi101846x.
S Lee, Y Xue, J Hulbert, Y Wang, X Liu, B Demeler, & Y Ha. The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization. United States. doi:10.1021/bi101846x.
S Lee, Y Xue, J Hulbert, Y Wang, X Liu, B Demeler, and Y Ha. Sat . "The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization". United States. doi:10.1021/bi101846x.
@article{osti_1041952,
title = {The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization},
author = {S Lee and Y Xue and J Hulbert and Y Wang and X Liu and B Demeler and Y Ha},
abstractNote = {Amyloid precursor protein (APP) is genetically linked to Alzheimer's disease. APP is a type I membrane protein, and its oligomeric structure is potentially important because this property may play a role in its function or affect the processing of the precursor by the secretases to generate amyloid {beta}-peptide. Several independent studies have shown that APP can form dimers in the cell, but how it dimerizes remains controversial. At least three regions of the precursor, including a centrally located and conserved domain called E2, have been proposed to contribute to dimerization. Here we report two new crystal structures of E2, one from APP and the other from APLP1, a mammalian APP homologue. Comparison with an earlier APP structure, which was determined in a different space group, shows that the E2 domains share a conserved and antiparallel mode of dimerization. Biophysical measurements in solution show that heparin binding induces E2 dimerization. The 2.1 {angstrom} resolution electron density map also reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. The locations of two of these residues, Arg-369 and His-433, at the dimeric interface suggest a mechanism for heparin-induced protein dimerization.},
doi = {10.1021/bi101846x},
journal = {Biochemistry (Eaton)},
issn = {0006-2960},
number = 24,
volume = 50,
place = {United States},
year = {2011},
month = {12}
}