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Alzheimer's amyloid precursor protein copper-binding domain

spinqualitylabelsall models PDB ID 2fkl Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
2fkl, resolution 2.50Å ()
Gene:	APP (Homo sapiens)
Related:	1owt, 2fjz, 2fk1, 2fk2, 2fk3
Structural annotation: Resources: InterPro : Ipr008154, Ipr013803, Ipr015849, Ipr011178, Ipr002223, Ipr008155 Pfam : PF02177 UniProt : P05067
Functional annotation: Cellular component: coated pit extracellular region integral to plasma membrane integral to membrane membrane cell surface Biological process: cell adhesion neuromuscular process apoptosis cellular copper ion homeostasis endocytosis Notch signaling pathway Molecular function: endopeptidase inhibitor activity identical protein binding binding protein binding serine-type endopeptidase inhibitor activity zinc ion binding heparin binding metal ion binding iron ion binding copper ion binding
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

Contents 1 Introduction 2 Structure 3 Additionnal Resources 4 References 5 Contributors

Introduction

2FKL is located in a transmembrane protein called APP for Amyloid precursor protein. This domain going from residue 124 to 189 is localized in the extracellular part of APP just between the Growth Factor Domain (GFD) and the Acidic domain, in a region called Cu-Binding Domain which is able to bind Cu and Zinc.

This proteins plays a major role into the development of Alzheimer disease^[1]. APP cleavage by BACE and gamma secretase gives ended rise to the Aβ peptide, which forms at the end an aggregation of amyloid plaques ^[2] .

As the interaction between copper ion and APP can modulate the production of Aβ peptide ^[3] and also the progression of Alzheimer disease, structural studies of the Cu-binding Domain of this protein give a lot of information for the development of novel therapeutics.

Structure

spinqualitylabelsall models 2fkl Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The three dimensional structure of the Cu-Binding Domain was first determined by resonance multidimensional NMR spectroscopy ^[4] PMID : 12611883 </ref>. More recently, the determination of the crystallographic structure permits to define the molecular interaction between the Cu-Binding Domain and copper.^[3]

2fkl is constituted by two chains called A and B^[4]

These plaques are concentrated with Aβ peptide which results from the anormal cleavage of APP by successive action of the β and γ secretases, illustrated on fig 3.The alteration in copper homostasis is directly related to the progression of Alzheimer disease. The impact of Cu(II) on the aggregation of Aβ peptide is still discussed even if Cu(II) is find in elevated concentration in these plaques. For more information you can follow the link : Alzheimer disease

The differents domains involved into the Aβ dimerisation aren't yet wery well known, but it seems that E1 and E2 are playing a major role. E1 contains the copper-binding site domain and also the Growth Factor-like Domain, rather than E2 contains the Central APP domain. Those two regions are located in the extracellurlar space. ^[5]

If the CuBD (located in E1 region) does contribute to APP dimerisation without Cu ions, that mean that the Cu binding may reduce Aβ production, either by shifting the monomer-dimer equilibrium to favor monomer form, or by re-orienting the dimer form, which disfavour the Aβ production. ^[3]

Additionnal Resources

PDB file of 2fkl
PDB file of 2fk1
PDB file of 2fk2
Alzheimer disease

References

1. ↑ Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PMID:12399581 doi:10.1126/science.1074069
2. ↑ Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. PMID:2881207 doi:http://dx.doi.org/10.1038/325733a0
3. ↑ ^{3.0 3.1 3.2} Kong GK, Miles LA, Crespi GA, Morton CJ, Ng HL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW. Copper binding to the Alzheimer's disease amyloid precursor protein. Eur Biophys J. 2008 Mar;37(3):269-79. Epub 2007 Nov 21. PMID:18030462 doi:10.1007/s00249-007-0234-3
4. ↑ ^{4.0 4.1} Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem. 2003 May 9;278(19):17401-7. Epub 2003 Feb 28. PMID:12611883 doi:10.1074/jbc.M300629200
5. ↑ Khalifa NB, Van Hees J, Tasiaux B, Huysseune S, Smith SO, Constantinescu SN, Octave JN, Kienlen-Campard P. What is the role of amyloid precursor protein dimerization? Cell Adh Migr. 2010 Apr-Jun;4(2):268-72. Epub 2010 Apr 11. PMID:20400860

Contributors

Milène Walter, Andréa Mc Cann