3QMK: Crystal Structure Of The E2 Domain Of Aplp1 In Complex With Heparin Hexasaccharide

Citation:
Abstract
Mutations in amyloid precursor protein (APP) are associated with familial Alzheimer's disease. Recent development suggests that homo- and heterodimerization of APP and APP-like proteins (APLPs), which are enhanced by heparan sulfate binding, may play a role in signal transduction and cell adhesion. Despite efforts to model heparin binding based on known apo crystal structures, the mechanism of heparin-induced APP/APLP dimerization has not been established experimentally. Here we report the crystal structure of a complex between heparin and the E2 domain of APLP1, which harbors the conserved high affinity heparin binding site of the full-length molecule. Within the asymmetric E2:heparin complex, the polysaccharide is snugly bound inside a narrow groove between the two helical subdomains of one protein protomer. The nonreducing end of the sugar is positioned near the protein's 2-fold axis, making contacts with basic residues from the second protomer. The inability of the E2 dimer to accommodate two heparin molecules near its symmetry axis explains the observed 21 binding stoichiometry, which is confirmed by isothermal titration calorimetric experiment carried out in solution. We also show that, at high concentrations, heparin can destabilize E2 dimer, probably by forcing into the unoccupied binding site observed in the 21 complex. The binding model suggested by the crystal structure may facilitate the design of heparin mimetics that are capable of modulating APP dimerization in cells.
PDB ID: 3QMKDownload
MMDB ID: 94236
PDB Deposition Date: 2011/2/4
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 2.21  Å
Source Organism:
Similar Structures:
Biological Unit for 3QMK: dimeric; determined by author and by software (PISA)
Molecular Components in 3QMK
Label Count Molecule
Proteins (2 molecules)
2
Amyloid-like Protein 1(Gene symbol: APLP1)
Molecule annotation
Chemicals (7 molecules)
1
2
2
2
3
3
* Click molecule labels to explore molecular sequence information.

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