3QMK

Crystal structure of the E2 domain of APLP1 in complex with heparin hexasaccharide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization.

Xue, Y.Lee, S.Ha, Y.

(2011) Proc Natl Acad Sci U S A 108: 16229-16234

  • DOI: https://doi.org/10.1073/pnas.1103407108
  • Primary Citation of Related Structures:  
    3QMK

  • PubMed 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.


  • Organizational Affiliation

    Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Amyloid-like protein 1
A, B
214Homo sapiensMutation(s): 0 
Gene Names: APLP1
UniProt & NIH Common Fund Data Resources
Find proteins for P51693 (Homo sapiens)
Explore P51693 
Go to UniProtKB:  P51693
PHAROS:  P51693
GTEx:  ENSG00000105290 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51693
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose
C
4N/A
Glycosylation Resources
GlyTouCan:  G35014IY
GlyCosmos:  G35014IY
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.223 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.183α = 90
b = 81.899β = 90
c = 90.79γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
PHASERphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2011-10-12 
  • Deposition Author(s): Xue, Y., Ha, Y.

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-12
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2024-02-21
    Changes: Data collection, Database references, Structure summary